Skip to main content
Download PDF

Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer

Molecular Cancer volume 24, Article number: 130 (2025) Cite this article

Abstract

Colorectal cancer (CRC) is stratified by heterogeneity between disease sites, with proximal right-sided CRC (RCRC) multifactorial in its distinction from distal left-sided CRC (LCRC). Notably, right-sided tumors are associated with aggressive disease characteristics which culminate in poor clinical outcomes for these patients. While factors such as mutational profile and patterns of metastasis have been suggested to contribute to differences in therapy response, the exact mechanisms through which RCRC resists effective treatment have yet to be elucidated. In response, recent analyzes, including those utilizing whole genome sequencing, transcriptional profiling, and single-cell analyses, have demonstrated that key molecular differences exist between disease sites, with differentially expressed genes spanning a diverse range of cellular functions. Here, we review and contextualize the most recent data on molecular biomarkers found to exhibit discordance between RCRC and LCRC, and highlight candidates for further investigation, including those which present promise for future clinical application. Given the present disparity in survival outcomes for RCRC patients, we expect the prognostic biomarkers presented in our review to be useful in establishing future directions for the side-specific treatment of CRC.

Clinical trial number

Not applicable

Background

Colorectal cancer (CRC) is the third most common malignancy worldwide, accounting for 9% of all cancer-related deaths [1, 2]. Tumors arising from the right (RCRC) and left (LCRC) sides of the colon are clinicopathologically distinct and demonstrate differing prognoses, with clinical studies consistently reporting RCRC patients as less responsive to both cytotoxic chemotherapeutics and targeted therapies [3, 4]. In the hope of improving patient outcomes and developing novel therapy options, the biological and molecular characteristics that underpin RCRC and LCRC must be elucidated.

Fundamental differences in the embryological origin of the right and left colon have been implicated in disease pathogenesis and subsequent treatment response. Molecularly, embryonic patterning of the developing colon is determined by the distinct expression of genes including those within the homeobox (HOX) and caudal-related homeobox (CDX) families [5]. Anatomically, the right colon arises from the embryonic midgut and comprises the caecum, ascending colon, hepatic flexure and proximal two thirds of the transverse colon, while the left colon arises from the hindgut and includes the distal third of the transverse colon, the splenic flexure, descending colon, and rectum, although the rectum has been considered to be of further biological distinction [5,6,7]. Vasculature and lymphatics develop concurrently and similarly service the colon depending on midgut or hindgut origin. Specifically, the midgut-derived right colon is supplied by the superior mesenteric artery and its branches, while the hindgut-derived left colon is supplied by the inferior mesenteric artery and its derivatives [5]. Lymphatic drainage follows the orientation of the arterial anatomy, while venous drainage of the right and left colon occurs through the superior and inferior mesenteric veins respectively [5, 8, 9]. Despite their similar arrangement, the combined vascular anatomy of the right colon displays more variation than that of the left, with notable differences in vessel orientation and the number of middle colic veins frequently differing between individuals [10,11,12].

In the context of CRC, the anatomical position of right-sided and left-sided tumors with respect to vasculature and lymphatics has been suggested to influence the route through which they metastasize. Specifically, while the liver and peritoneum are the most common sites of metastasis across primary tumor locations [13], the former represents a higher proportion within LCRC, with RCRC more commonly involving the peritoneum [14,15,16]. As compared to the likely hematogenous spread of liver metastases [13, 17], peritoneal metastases, which represent distinctly poor outcomes for CRC patients [18], are thought to arise, at least in part, by way of the lymphatic system [13, 19], with drainage of the peritoneal cavity expected to include superior mesenteric lymph nodes along the right colon, based on animal studies [20]. Coupled with the increased likelihood of RCRC being of T4 staging [21, 22], whereby disease extends into the visceral peritoneum [23], as well as colectomy enabling the release of potentially metastatic cells into the peritoneal cavity [24], the lymphatic drainage of the right colon only further facilitates the progression of disease within the peritoneum.

Genetically, key drivers of tumor formation have been seen to differ between RCRC and LCRC, though it remains unclear what role anatomical variation plays in initiating or supporting this growth. Pathogenesis of disease originating from the left side of the colon has long been associated with a conventional “adenoma-to-carcinoma sequence”, characterized by microsatellite stability (MSS) and the sequential accumulation of mutations in genes including APC, KRAS and TP53 [25, 26]. Meanwhile, RCRC is more commonly associated with the serrated pathway of carcinogenesis, with microsatellite instability (MSI) and mutations in the BRAF gene often inciting poorly differentiated lesions of inferior visibility on colonoscope, increasing the difficulty of timely detection [27,28,29,30,31]. In spite of these associations, the carcinogenic pathways driving RCRC and LCRC are not mutually exclusive, with lesions representing both the conventional and serrated pathways observed across disease sites, albeit observed in different frequencies [32], thus aligning with the idea of a mutational continuum [33]. A recent genomic analysis of over 2000 colorectal tumors has provided comprehensive insight into this hypothesis, with disease further subdivided based on the genomic stability of MSS tumors. While the authors indeed associate MSI with RCRC, they reveal MSS disease of the right side as more likely to be genomically stable, with MSS left-sided disease more commonly associated with whole genome duplication and loss of heterozygosity. Meanwhile, their analysis of MSS tumors across disease sites demonstrated a decrease in the mutation of IDI1, ID2, KRAS and PIK3CA and an increase in TP53 mutations in LCRC [34].

The distribution of tumor mutational profiles and the identification of actionable driver genes is key to assessing and assigning therapeutic regimes (Fig. 1). Unfortunately, current associations of clinical response with tumor sidedness negate the mutational and transcriptional spectra within which each side of disease lies. For instance, clinical trials assessing the response of patients to anti-EGFR and anti-VEGF therapies display variable results between RCRC and LCRC, with poorer outcomes observed in RCRC patients, both when treated with anti-EGFR therapies and when treated with anti-VEGF therapies. While this has been attributed to the reduced activity of both EGFR and VEGF-1 in right-sided disease [3, 30, 35], the increased prevalence of KRAS and BRAF mutants in RCRC, suggest these pathways are active in these patients rather than RCRC patients are collectively less responsive to these agents. Regardless, the observation of RCRC as less responsive to anti-EGFR than anti-VEGF therapies [36] is reflected in the European Society for Molecular Oncology (ESMO) Clinical Practice Guidelines for CRC treatment, where RCRC and RAS-mutant patients are recommended combination therapies inclusive of bevacizumab (anti-VEGF), while LCRC, RAS-wildtype patients are recommended anti-EGFR therapies [37].

Fig. 1
figure 1

Distribution of clinically relevant biomarkers and approved therapeutic targets between sides. While RCRC is associated with CMS1 and CMS3 profiles, as well as BRAF, KRAS, and PIK3CA mutations, LCRC is associated with CMS2 and CMS4 status, alongside TP53 mutations. Of the targeted therapies currently approved by the United States Food and Drug Administration for the treatment of CRC, the increased incidence of MSI in right-sided disease dictates RCRC patients as more receptive to immunotherapies, including ipilimumab (anti-CTLA-4), nivolumab (anti-PD-1) and pembrolizumab (anti-PD-1). Such is also the case with mutant forms of the KRAS (G12C) and BRAF (V600E, V600D, V600K) proteins, which favor LCRC and RCRC, respectively. Meanwhile, the increased expression of targets including HER2 (tucatinib), VEGF (bevacizumab, ziv-aflibercept) and EGFR (cetuximab, panitumumab) in LCRC align with the superior response of these patients to the corresponding therapies. Even so, bevacizumab has been demonstrated as more efficacious in RCRC than anti-EGFR therapies or chemotherapy alone, and as such, is recommended for the treatment of both right-sided and RAS-mutant disease. Data were retrieved from and based on references [3, 30, 32, 34,35,36, 38,39,40,41,42,43,44,45,46]

Full size image

While classification systems, such as the consensus molecular subtype (CMS), have been designed to better categorize patients based on tumor and stromal characteristics, they too provide an imperfect method to segregate patient groups and, as intra-tumoral heterogeneity precludes the ascription of a singular phenotype, have yet to make a marked impact on personalized cancer medicine [47, 48]. Furthermore, although RCRC tumors have been seen to align with the CMS1 and CMS3 profiles, and LCRC with CMS2 and CMS4, current targeted therapies are limited to antagonizing a single antigen, rather than the myriad of mutations associated with each CMS subtype, so are incompatible with such a broad approach [33, 46]. Therefore, in order to better tailor side-specific treatment options, we must first deduce the distinct, targetable molecular attributes of right-sided and left-sided disease.

The distinction between RCRC and LCRC is being made progressively clearer by virtue of greater accessibility to whole genome and RNA sequencing, and the subsequent development of large cancer datasets. These datasets, such as the commonly referenced The Cancer Genome Atlas, enable researchers to construct high confidence estimations of transcriptional and translational relationships, as well as to simply define genes that are differentially expressed between two conditions [49,50,51,52,53,54]. Additionally, independent datasets compiled from institutional patient tissue repositories provide further opportunity for discovery, whilst are also commonly combined with publicly available datasets for more robust and comprehensive analyses [55]. Accordingly, this review aims to encapsulate recent advances in the molecular characterization of right and left CRC, focusing primarily on observed differences in gene and protein expression.

Transcriptional regulators linked to poor clinical outcomes are commonly associated with RCRC

Perturbed gene expression promotes cancer initiation and drives progression [56]. As transcriptional regulators contribute to the maintenance of a neoplastic cell state, key genomic and proteomic instigators have been studied both for their influence on genetic reprogramming, and their ability to be targeted in pursuit of restoring transcriptional homeostasis [57]. Epigenetic modifiers and nucleic acid binding proteins, including transcription factors, are proteins of functional relevance, while certain forms of RNA, including long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs), have also been implicated in cancer-associated gene regulation. This has been further deciphered with the advent of single-cell (scRNAseq) and spatial profiling to reveal interactions within the tumor microenvironment of left- and right-sided disease [58].

Among the proteins identified as differentially expressed between RCRC and LCRC (Table 1), PRAC1, a small nuclear protein, has been frequently referenced to be of higher expression in LCRC [49, 51,52,53, 59]. However, given that PRAC1 has been reported to not be correlated with patient outcome in either side [60], and its repression in the right side is expected to be the result of hypermethylation [49], further work is required to determine whether PRAC1 is truly oncogenic in the left side of the colon, or just exclusively expressed in the region. PRAC1 has also been speculated to be co-transcribed with the HOXB13 gene, which itself has been reported as being of higher expression in LCRC [54, 60, 61]. Interestingly, although of higher expression in LCRC, HOXB13 expression was observed to be associated with improved patient outcomes in RCRC only, where it was distinct from LCRC in exhibiting differential expression from normal tissue specimens [60]. HOXB13 was also found to be tumor suppressive in vitro [60], further highlighting its potential as a candidate gene for targeted therapeutic intervention.

Additional members of the HOX family of transcription factors, HOXC4, HOXC6 and HOXC8, have also been found to be differentially expressed between RCRC and LCRC, although unlike HOXB13, they demonstrate greater expression in disease affecting the right side of the colon [51,52,53,54, 59]. Like PRAC1, HOXC6 specifically is frequently reported as one of the most differentially expressed genes [51,52,53,54, 59] (Table 1), and, notably, has been linked to epithelial-to-mesenchymal transition (EMT) and tumor proliferation in various malignancies, including CRC [62,63,64,65,66]. In cervical cancer, experimental silencing of HOXC6 with small interfering RNA (siRNA) was seen to inhibit EMT through the TGF-b signaling pathway [62], however in CRC, HOXC6-related proliferation [63] and EMT [64] were found to require mTOR and Wnt signaling, respectively, suggesting a multifaceted, and potentially plastic, role of HOXC6 in disease progression. Furthermore, HOXC6 expression has also been related to the cellular composition of the tumor microenvironment (TME), with immune infiltration higher in patients with increased HOXC6 expression [66]. Although such infiltration is characteristic of RCRC generally [67], other RCRC-associated traits, such as high expression of immune checkpoint markers [66], were similarly observed in high HOXC6-expressing glioma cells, which, strikingly, suggests that HOXC6 may be supporting the aggressive pathogenesis of RCRC through pan-cancer mechanisms [63].

In further relation to the TME, cancer-associated fibroblasts (CAFs) have also been implicated in the expression of HOXC6. Specifically, CAF-derived extracellular vesicles containing the lncRNA SNHG3 have been found to increase the expression of HOXC6, inciting greater tumor proliferation [68]. Alongside this particular study, which emphasized the role of the mesenchymal niche in supporting CRC growth, other work has also reported the differential expression of various lncRNAs between RCRC and LCRC [50, 51, 55, 59]. However, the function of many has yet to be determined, thus representing the need for further investigation. Similarly, miRNAs are also commonly reported as differentially expressed, including the findings described by Eneh and colleagues [69], but again require more detailed characterization and experimental validation [70].

Alongside HOXC6, whereby gene silencing was seen to increase CRC cell sensitivity to irinotecan [66], a recent study has shown that knockdown of FOXD1, another transcription factor also of higher expression in RCRC [53, 54], increases sensitivity to oxaliplatin both in vitro and in vivo [71]. Although this was cited as relative to increased cell stemness and the exact mechanism not determined, FOXD1 has otherwise been described as a promoter of CRC cell proliferation through regulation of the polo-like kinase 2 protein [72], which itself has been associated with chemoresistance in CRC [73]. While transcription factors have historically been difficult targets for novel cancer therapies [74], they nevertheless provide the opportunity for more personalized patient prognostication and prediction of therapy response.

Such is also the case for other nucleic acid binding proteins, including SATB2 [50, 75, 76], which facilitates transcription through the induction of chromatin loops, and whose loss is associated with poor prognosis and right sidedness. Similarly, the expression of R-loop binding proteins, which help to maintain genomic stability, has been observed to cluster into categories of low and high expression, with low expression again associated with poor prognosis and right sidedness [77]. Interestingly, the loss of ELAVL2, whose protein binds and stabilizes mRNA, is also associated with right sidedness [50, 53], as well as aggressive tumor behavior in other cancer types [78, 79]. Whilst dysregulation of nucleic acid binding proteins and other transcriptional regulators is not a feature of RCRC, genes associated with aggressive disease are frequently reported to be of significant difference between right and left tumor sites, and as demonstrated, are more commonly associated with right-sided primary tumor location.

Table 1 Differentially expressed genes related to transcriptional regulation
Full size table

Tumor metabolism and cell signaling is likely confounded by the side-dependent genomic landscape of CRC

Metabolic reprogramming is associated with CRC growth, progression and chemoresistance, and is dependent on the specific mutational profile of a patient’s tumor. Namely, Wnt, MAPK, PI3K and p53 signaling have all been individually implicated in aberrant metabolic processes [82, 83], with further changes observed in response to chemotherapeutic treatment [84, 85]. While side-associated disease characteristics, such as RCRC-linked BRAF mutation, are therefore likely to contribute to observed differences in metabolic gene expression (Table 2), these markers provide a foundation for future investigative and mechanistic research nonetheless. Interestingly, ligands of commonly mutated signaling pathways have been reported to be differentially expressed, including activin A in RCRC [86] and LEFTY1 in LCRC [54], while signaling antagonists, such as DKK4 in RCRC [54] and WIF1 in LCRC [51], were also noted, indicating possibly side-exclusive mechanisms through which these pathways contribute to disease pathogenesis and progression. The genes referenced in these studies also corroborate the diversity of signaling pathways altered in RCRC and LCRC, as mentioned in relation to transcriptional regulators, with Wnt, BMP and TGF-b interactors all highlighted between disease sites [51, 54, 55, 86]. Otherwise, genes such as FABP1 reinforce the clinicopathological differences existing between RCRC and LCRC, such that FABP1 is commonly used as a marker of differentiated enterocytes [87, 88] and aligns with the greater differentiation of left-sided tumors [30, 31]. Meanwhile, the upregulation of TRIM29 in RCRC again aligns with the aggressive nature of right-sided disease, given TRIM29 has been linked to an increased risk of recurrence and death, exclusively in RCRC [89]. Other studies have also demonstrated the carcinogenic role of TRIM29 in CRC, with overexpression resulting in increased cell invasion and migration both in vitro and in mouse models [90], in addition to knockdown preventing disease progression [90, 91]. Such was similarly observed in pancreatic ductal adenocarcinoma cells lines, whereby overexpression was also found to promote resistance to the chemotherapeutic agent gemcitabine by increasing DNA synthesis [92], with an additional study also relating TRIM29 to DNA damage repair [93]. Interestingly, TRIM29 overexpression has also been demonstrated to resensitize an oxaliplatin-resistant CRC cell line [94], although, given this was related to TP53 mutant status, of which the TRIM29 protein is not dependent [95] and which is less commonly observed in RCRC [34, 38], further research is necessary to confirm this phenomenon in TP53 wildtype tumors.

Table 2 Differentially expressed genes related to cellular metabolism and signaling
Full size table

Side-related genes involved in tumor cell architecture are linked to disease pathogenesis and therapy resistance

The intricate interplay of cell adhesion and structural proteins within a tumor determines its ability to proliferate and progress within the greater microenvironmental context. Genes encoding structural proteins, such as CNTRL and MAST1, are among those reported as differentially expressed between RCRC and LCRC (Table 3), however most have yet to be experimentally validated beyond the context of RNA sequencing [50, 59]. Nevertheless, several have been linked to a cancer setting in other studies, including NRP1 [102], KRT23 [103], SPRR1A [104] and MAST1 [105]. Notably, elevated MAST1 expression has been implicated in platinum-based chemotherapy resistance, with MAST1 inhibition shown to restore cisplatin sensitivity in vitro [105].

Additionally, a cohort of cell membrane proteins that contribute to tumor structure, as well as to intracellular and intercellular signaling, have also been reported to exhibit differential expression between RCRC and LCRC. Of note, LY6G6D, which encodes a membrane protein of the major histocompatibility complex (MHC) family, has been reported to be of higher expression in LCRC [53, 54], as has related gene XXbac-BPG32J3.19 [53]. LY6G6D, however, has been demonstrated to be selectively expressed in MSS CRC cells [106], meaning that the increased expression observed in LCRC is likely attributed to the predominance of MSS disease within the left side. Given LY6G6D has also been implicated in the immune resistance that is characteristic of MSS disease [107], targeting LY6G6D may provide a novel opportunity for the treatment of MSS CRC patients.

The expression of certain membrane markers, when linked to poor prognosis, are also often associated with right-sided tumor location. Such is the case with MUC12, a membrane glycoprotein gene related to barrier function, whereby low expression has been related to poor disease-free survival outcomes [108], and which has been reported as of lower expression in RCRC [52, 54]. Similarly, a reduction in DAB2 expression, which encodes an endocytosis-regulating transmembrane protein, has been related with disease progression [109] and has recently been shown to be lowly expressed in high-grade and right-sided tumors [110]. Interestingly, DAB2 has also emerged as a potential contributor to immune suppression. Like LY6G6D, DAB2 is associated with the low neoantigen load characteristic of LCRC and also interferes with tissue-resident immune cell signaling [111]. This suggests that varying levels of DAB2 expression, both high and low, may play a role in distinguishing between right-sided and left-sided disease.

Table 3 Differentially expressed genes related to cell membrane and structure
Full size table

Differing immune and microbial profiles define RCRC and LCRC, even when accounting for microsatellite instability

As a result of the higher mutational burden of RCRC, usually incited by MSI and deficient mismatch repair (MMR) proteins, RCRC is often associated with greater immune infiltration and improved response to immunotherapies, such as anti-PD-1 [65, 115]. So, while left-sided disease has been found to be of greater tumor purity, RCRC has instead been correlated with a greater immune score, including higher counts of a variety of lymphoid cells [55, 116, 117] (Fig. 2). Similarly, the expression of immune-checkpoint and human leukocytic antigen (HLA) related genes has also been found to be increased in right-sided disease [55], alongside various other immune-related markers (Table 4). In explication of these associations, a recent study utilizing an existing scRNAseq dataset revealed two side-dependent meta-programs which influence the immune landscape of RCRC and LCRC [118]. Specifically, they define a LCRC-associated proliferation stemness (PS) meta-program linked to cell cycle progression genes and stem cell identity, and an RCRC-associated immune secretory (IS) meta-program linked to the expression of MHC class II molecules, including HLA genes. While the PS meta-program was associated with activated regulatory T cells (Tregs) in LCRC and the IS meta-program associated with attenuated CD161-positive CD8-positive T cells in RCRC, for example, further analysis is required to conclude that these programs are indeed side-dependent after accounting for MSI-related differences known to exist between sides.

Clinically, the prognostic value of specific immune cells and their relative proportions also differ between RCRC and LCRC. For instance, while activated tissue resident memory T cells have been shown to be predictive of good prognosis in LCRC patients, the same cells indicate poor prognosis in RCRC [119]. Similarly, the ratio of lymphocytes to monocytes has been found to be higher in LCRC, although this is only predictive of prolonged survival in RCRC patients [120]. Interestingly, Foxp3, a marker of Tregs [121], has been reported to correlate with poor prognosis in LCRC patients only [122], while at the same time, CD39-positive γδ T cells, a subset of Tregs [123], have been shown to be increased in right-sided disease [97], indicating differing mechanisms of immune suppression. Specifically, these CD39-positive γδ Tregs have been associated with the activation of the phospholipase A2-IVA/arachidonic acid (PLA2G4A/AA) metabolic pathway exclusively in RCRC [97]. Meanwhile, CD4-positive T cells, including populations of Tregs, have been shown to be more functional in left-sided disease, also in part due to metabolic factors [124]. This further suggests a difference in immune activity between sides that extends beyond microsatellite stability and mismatch repair status.

Also active within the TME, mesenchymal niche cells, such as CAFs, have been determined to contribute to CRC carcinogenesis and progression [125], but the difference between RCRC and LCRC populations remains to be elucidated [126]. Differences in the microbiota of those with RCRC and LCRC, however, has been studied more thoroughly [127, 128], although contention still remains when defining side-dominant genera. For instance, where Fusobacterium has been linked to poor prognosis and RCRC mucosa by Jin et al. [129], it has also been shown to predominate the fecal microbiota in LCRC by Miyake et al. [130]. Meanwhile, studies by Du et al. have described an association between the presence of Fusobacterium and a favorable prognosis [53]. In their recent large-scale analysis of colorectal tumors, Cornish et al. clarify side-dominant genera, particularly Fusobacterium, to not only differ between sides, but also between MSI and MSS tumors [34]. While their cohort of left-sided MSI tumors was of insufficient size for comparison, the proportion of Fusobacterium in right-sided MSI tumors was significantly higher than in right-sided MSS tumors, with both of significantly greater proportion than MSS left-sided tumors, although Fusobacterium remained among the most predominant genera in all tumors. Meanwhile, the proportion of Akkermansia bacteria was found to be greater in left-sided tumors, as previously reported by Kolisnik et al. [59].

To relate this to prognosis, various side-related microbial genera have been associated with chemotherapy response in pre-clinical studies. Specifically, RCRC-associated Fusobacterium nucleatum has been linked to 5-fluorouracil (5-FU) and oxaliplatin chemoresistance through toll-like receptor 4 (TLR4)-mediated autophagy [131], with BIRC3 later implicated in the same mechanism of 5-FU resistance [132]. Meanwhile, Fusobacterium nucleatum has also been observed to promote anti-PD-1 immunotherapy resistance through the release of succinic acid, a molecule which was shown to reduce CD8-positive T cell count in a murine model [133]. Otherwise, Prevotella, which has also been associated with RCRC, has similarly been observed to contribute to 5-FU-based chemotherapy resistance and disease progression [134, 135], while, on the other hand, LCRC-linked Akkermansia muciniphila has been evidenced to potentiate the efficacy of 5-FU and oxaliplatin [136] and RCRC-linked Firmicutes [137] has been associated with improved patient survival [138].

In translation to the clinic, various studies have assessed the effect of probiotics and fecal microbiota transplants (FMT) on the efficacy of standard adjuvant therapies [139], however these have attempted to restore microbial homeostasis within the gut, rather than target specific bacterial populations. The vastly reduced microbial load of metastatic disease [34], in addition to difficulty in targeting microbiota at sites of metastasis [140], presents the ongoing challenge of how best to modulate bacteria beyond the colon. The higher bacterial load of RCRC [34], which mirrors the increased homeostatic abundance of bacteria in the right colon [141], presents the attractive prospect of antimicrobial agents being used to bolster anti-tumor efficacy [142], but such treatment poses the risk of off-target disruption of an already diminished colonic flora [139, 143]. Nevertheless, the complex interplay between tumor-promoting and tumor-protective microbiota, and their joint influence on chemosensitivity, suggests microbial modulation as a potential therapeutic opportunity for both RCRC and LCRC [144], with further research to determine the feasibility of clinical application.

Fig. 2
figure 2

Sidedness-associated differences in immune and bacterial abundance within the tumor microenvironment. While LCRC is associated with disease characterized by polypoid adenocarcinomas and chromosomal instability, RCRC is conversely associated with serrated tumor morphology and MSI. On account of the MSI phenotype, immune infiltration is often reported as higher in RCRC, as is the immune and stromal conjugate ESTIMATE score, while tumor purity is accordingly greater in left-sided disease. Even so, certain subsets of immune cells, including natural killer (NK) cells and memory B cells, have been reported as more abundant in LCRC. Meanwhile, the predominant microbiota of RCRC and LCRC tumors have been presented as distinct, with the often RCRC-associated Fusobacterium reported to also dominate the LCRC flora, in addition to the description of various other bacteria as differentially abundant between sides. Data were retrieved from and based on references [34, 55, 59, 67, 97, 117, 124, 127, 129, 130, 137]

Full size image
Table 4 Differentially expressed genes related to tumor microenvironment
Full size table

Conclusions

Recent studies evaluating the differential gene expression of RCRC and LCRC tumors have reported a variety of targets encompassing a range of cellular functions. In this review, we summarized genes, proteins and cell types that represent significant variation between sides, and highlighted candidates for further investigation, including those that have been linked to disease progression and therapy resistance. Importantly, it is clear that differentially expressed genes associated with aggressive disease characteristics and poor patient outcomes are more often associated with RCRC. However, given differences in the distribution of key driver mutations between sides, as well as the varied impact of microsatellite instability and DNA mismatch repair protein deficiency, this review also highlights the need for added comparisons which extend beyond the fundamental anatomical differences of the colon. Additionally, experimental validation of gene targets identified through RNA sequencing will assist in confirming both their association and role in mediating differences in patient prognosis, with innovative spatial profiling to enable such investigation in the context of side-dependent microenvironmental niches. These future studies will likely inform the development of novel side-specific therapy options and improved patient outcomes.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

5-FU:

5-flurouracil

APC:

Adenomatous polyposis coli

BMP:

Bone morphogenetic protein

BRAF:

v-raf murine sarcoma viral oncogene homolog B1

CAF:

Cancer-associated fibroblast

CDX:

Caudal-related homeobox

CMS:

Consensus molecular subtype

CNTRL:

Centriolin

CRC:

Colorectal cancer

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DAB2:

Disabled-2

DKK4:

Dickkopf-4

EGFR:

Epidermal growth factor receptor

ELAVL2:

ELAV like RNA binding protein 2

EMT:

Epithelial-mesenchymal transition

ESTIMATE:

Estimation of stromal and immune cells in malignant tumor tissues using expression data

FABP1:

Fatty acid binding protein 1

FMT:

Fecal microbiota transplant

FOXD1:

Forkhead box D1

HER2:

Human epidermal growth factor 2

HLA:

Human leukocyte antigen

HOX:

Homeobox

ID2:

Inhibitor of DNA binding 2

IDI1:

Isopentenyl-diphosphate delta isomerase 1

IS:

Immune secretory

KRAS:

Kristen rat sarcoma viral oncogene homolog

KRT23:

Keratin 23

LCRC:

Left colorectal cancer

LEFTY1:

left-right determination factor 1

lncRNA:

Long non-coding RNA

LY6G6D:

Lymphocyte antigen 6 complex

MAPK:

Mitogen-activated protein kinase

MAST1:

Microtubule associated serine/threonine kinase 1

MHC:

Major histocompatibility complex

miRNA:

Micro RNA

MMR:

Mismatch repair

mRNA:

Messenger RNA

MSI:

Microsatellite instable

MSS:

Microsatellite stable

mTOR:

Mammalian target of rapamycin

MUC12:

Mucin 12

NK:

Natural killer

NRP1:

Neuropilin 1

PD-1:

Programmed cell death protein 1

PI3K:

Phosphatidylinositol-3 kinase

PIK3CA:

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

PLA3G4A/AA:

Phospholipase A2-IVA/arachidonic acid

PRAC1:

Prostate cancer susceptibility candidate 1

PS:

Proliferation secretory

RCRC:

Right colorectal cancer

SATB2:

Special AT-rich sequence-binding protein 2

scRNAseq:

Single-cell RNA-sequencing

siRNA:

Small interfering RNA

SNHG3:

Small nucleolar RNA host gene 3

SPRR1A:

Small proline rich protein 1 A

TGF:

Transforming growth factor

TLR4:

Toll-like receptor 4

TME:

Tumor microenvironment

TP53:

Tumor protein p53

Tregs:

Regulatory T cells

TRIM29:

Tripartite motif-containing 29 protein

VEGF:

Vascular endothelial growth factor

WIF1:

Wnt inhibitory factor 1

References

  1. Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72(2):338–44.

    Article  PubMed  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  3. You XH, Jiang YH, Fang Z, Sun F, Li Y, Wang W et al. Chemotherapy plus bevacizumab as an optimal first-line therapeutic treatment for patients with right-sided metastatic colon cancer: a meta-analysis of first-line clinical trials. ESMO Open. 2020;4(Suppl 2).

  4. Mendis S, Beck S, Lee B, Lee M, Wong R, Kosmider S, et al. Right versus left sided metastatic colorectal cancer: teasing out clinicopathologic drivers of disparity in survival. Asia Pac J Clin Oncol. 2019;15(3):136–43.

    Article  PubMed  Google Scholar 

  5. Kostouros A, Koliarakis I, Natsis K, Spandidos DA, Tsatsakis A, Tsiaoussis J. Large intestine embryogenesis: molecular pathways and related disorders (Review). Int J Mol Med. 2020;46(1):27–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tamas K, Walenkamp AM, de Vries EG, van Vugt MA, Beets-Tan RG, van Etten B, et al. Rectal and colon cancer: not just a different anatomic site. Cancer Treat Rev. 2015;41(8):671–9.

    Article  CAS  PubMed  Google Scholar 

  7. Kodama H, Masuishi T, Wakabayashi M, Nakata A, Kumanishi R, Nakazawa T, et al. Differential efficacy of targeted monoclonal antibodies in Left-Sided Colon and rectal metastatic cancers. Clin Colorectal Cancer. 2023;22(3):298–306.

    Article  PubMed  Google Scholar 

  8. Denham LJ, Kerstetter JC, Herrmann PC. The complexity of the count: considerations regarding lymph node evaluation in colorectal carcinoma. J Gastrointest Oncol. 2012;3(4):342–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Cho HS, Ahn JH. Nomenclature and lymphatic drainage patterns of abdominal lymph nodes. J Korean Soc Radiol. 2022;83(6):1240–58.

    Article  PubMed  Google Scholar 

  10. Mike M, Kano N. Reappraisal of the vascular anatomy of the colon and consequences for the definition of surgical resection. Dig Surg. 2013;30(4–6):383–92.

    Article  PubMed  Google Scholar 

  11. Yamaguchi S, Kuroyanagi H, Milsom JW, Sim R, Shimada H. Venous anatomy of the right colon: precise structure of the major veins and Gastrocolic trunk in 58 cadavers. Dis Colon Rectum. 2002;45(10):1337–40.

    Article  PubMed  Google Scholar 

  12. Wu C, Ye K, Wu Y, Chen Q, Xu J, Lin J, et al. Variations in right colic vascular anatomy observed during laparoscopic right colectomy. World J Surg Oncol. 2019;17(1):16.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Pretzsch E, Bosch F, Neumann J, Ganschow P, Bazhin A, Guba M, et al. Mechanisms of metastasis in colorectal Cancer and metastatic organotropism: hematogenous versus peritoneal spread. J Oncol. 2019;2019:7407190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hugen N, van de Velde CJH, de Wilt JHW, Nagtegaal ID. Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol. 2014;25(3):651–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hugen N, Nagtegaal ID. Distinct metastatic patterns in colorectal cancer patients based on primary tumour location. Eur J Cancer. 2017;75:3–4.

    Article  PubMed  Google Scholar 

  16. Brouwer NPM, van der Kruijssen DEW, Hugen N, de Hingh I, Nagtegaal ID, Verhoeven RHA, et al. The impact of primary tumor location in synchronous metastatic colorectal cancer: differences in metastatic sites and survival. Ann Surg Oncol. 2020;27(5):1580–8.

    Article  PubMed  Google Scholar 

  17. Kow AWC. Hepatic metastasis from colorectal cancer. J Gastrointest Oncol. 2019;10(6):1274–98.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Franko J, Shi Q, Meyers JP, Maughan TS, Adams RA, Seymour MT, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the analysis and research in cancers of the digestive system (ARCAD) database. Lancet Oncol. 2016;17(12):1709–19.

    Article  PubMed  Google Scholar 

  19. Bootsma S, Bijlsma MF, Vermeulen L. The molecular biology of peritoneal metastatic disease. EMBO Mol Med. 2023;15(3):e15914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Parungo CP, Soybel DI, Colson YL, Kim SW, Ohnishi S, DeGrand AM, et al. Lymphatic drainage of the peritoneal space: a pattern dependent on bowel lymphatics. Ann Surg Oncol. 2007;14(2):286–98.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ghazi S, Lindforss U, Lindberg G, Berg E, Lindblom A, Papadogiannakis N, et al. Analysis of colorectal cancer morphology in relation to sex, age, location, and family history. J Gastroenterol. 2012;47(6):619–34.

    Article  PubMed  Google Scholar 

  22. Lee GH, Malietzis G, Askari A, Bernardo D, Al-Hassi HO, Clark SK. Is right-sided colon cancer different to left-sided colorectal cancer? - a systematic review. Eur J Surg Oncol. 2015;41(3):300–8.

    Article  CAS  PubMed  Google Scholar 

  23. Klaver CEL, van Huijgevoort NCM, de Buck A, Wolthuis AM, Tanis PJ, van der Bilt JDW, et al. Locally advanced colorectal cancer: true peritoneal tumor penetration is associated with peritoneal metastases. Ann Surg Oncol. 2018;25(1):212–20.

    Article  PubMed  Google Scholar 

  24. Kranenburg O, van der Speeten K, de Hingh I. Peritoneal metastases from colorectal cancer: defining and addressing the challenges. Front Oncol. 2021;11:650098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pancione M, Remo A, Colantuoni V. Genetic and epigenetic events generate multiple pathways in colorectal cancer progression. Patholog Res Int. 2012;2012:509348.

    PubMed  PubMed Central  Google Scholar 

  26. Yamagishi H, Kuroda H, Imai Y, Hiraishi H. Molecular pathogenesis of sporadic colorectal cancers. Chin J Cancer. 2016;35:4.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology. 2010;138(6):2088–100.

    Article  CAS  PubMed  Google Scholar 

  28. Yamane L, Scapulatempo-Neto C, Reis RM, Guimaraes DP. Serrated pathway in colorectal carcinogenesis. World J Gastroenterol. 2014;20(10):2634–40.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Pai RK, Bettington M, Srivastava A, Rosty C. An update on the morphology and molecular pathology of serrated colorectal polyps and associated carcinomas. Mod Pathol. 2019;32(10):1390–415.

    Article  PubMed  Google Scholar 

  30. Missiaglia E, Jacobs B, D’Ario G, Di Narzo AF, Soneson C, Budinska E, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol. 2014;25(10):1995–2001.

    Article  CAS  PubMed  Google Scholar 

  31. Asghari-Jafarabadi M, Wilkins S, Plazzer JP, Yap R, McMurrick PJ. Prognostic factors and survival disparities in right-sided versus left-sided colon cancer. Sci Rep. 2024;14(1):12306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kang S, Na Y, Joung SY, Lee SI, Oh SC, Min BW. The significance of microsatellite instability in colorectal cancer after controlling for clinicopathological factors. Med (Baltim). 2018;97(9):e0019.

    Article  CAS  Google Scholar 

  33. Loree JM, Pereira AAL, Lam M, Willauer AN, Raghav K, Dasari A, et al. Classifying colorectal Cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes. Clin Cancer Res. 2018;24(5):1062–72.

    Article  CAS  PubMed  Google Scholar 

  34. Cornish AJ, Gruber AJ, Kinnersley B, Chubb D, Frangou A, Caravagna G et al. The genomic landscape of 2,023 colorectal cancers. Nature. 2024.

  35. Bendardaf R, Buhmeida A, Hilska M, Laato M, Syrjanen S, Syrjanen K, et al. VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival. Anticancer Res. 2008;28(6B):3865–70.

    PubMed  Google Scholar 

  36. Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. Eur J Cancer. 2017;70:87–98.

    Article  PubMed  Google Scholar 

  37. Cervantes A, Adam R, Rosello S, Arnold D, Normanno N, Taieb J, et al. Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10–32.

    Article  CAS  PubMed  Google Scholar 

  38. Ciepiela I, Szczepaniak M, Ciepiela P, Hincza-Nowak K, Kopczynski J, Macek P, et al. Tumor location matters, next generation sequencing mutation profiling of left-sided, rectal, and right-sided colorectal tumors in 552 patients. Sci Rep. 2024;14(1):4619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schirripa M, Nappo F, Cremolini C, Salvatore L, Rossini D, Bensi M, et al. KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population. Clin Colorectal Cancer. 2020;19(3):219–25.

    Article  PubMed  Google Scholar 

  40. Andre T, Elez E, Van Cutsem E, Jensen LH, Bennouna J, Mendez G, et al. Nivolumab plus ipilimumab in Microsatellite-Instability-High metastatic colorectal Cancer. N Engl J Med. 2024;391(21):2014–26.

    Article  CAS  PubMed  Google Scholar 

  41. Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in Microsatellite-Instability-High advanced colorectal Cancer. N Engl J Med. 2020;383(23):2207–18.

    Article  CAS  PubMed  Google Scholar 

  42. Yasui H, Okita Y, Nakamura M, Sagawa T, Watanabe T, Kataoka K, et al. Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16. ESMO Open. 2023;8(5):101636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yoon SE, Lee SJ, Lee J, Park SH, Park JO, Lim HY, et al. The impact of primary tumor sidedness on the effect of regorafenib in refractory metastatic colorectal Cancer. J Cancer. 2019;10(7):1611–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zheng-Lin B, Bekaii-Saab TS. Treatment options for HER2-expressing colorectal cancer: updates and recent approvals. Ther Adv Med Oncol. 2024;16:17588359231225037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Underwood PW, Ruff SM, Pawlik TM. Update on targeted therapy and immunotherapy for metastatic colorectal Cancer. Cells. 2024;13(3).

  46. Lee MS, Menter DG, Kopetz S. Right versus left Colon cancer biology: integrating the consensus molecular subtypes. J Natl Compr Canc Netw. 2017;15(3):411–9.

    Article  PubMed  Google Scholar 

  47. Marisa L, Blum Y, Taieb J, Ayadi M, Pilati C, Le Malicot K, et al. Intratumor CMS heterogeneity impacts patient prognosis in localized Colon cancer. Clin Cancer Res. 2021;27(17):4768–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Koulis C, Yap R, Engel R, Jarde T, Wilkins S, Solon G et al. Personalized Medicine-Current and emerging predictive and prognostic biomarkers in colorectal Cancer. Cancers (Basel). 2020;12(4).

  49. Hu W, Yang Y, Li X, Huang M, Xu F, Ge W, et al. Multi-omics approach reveals distinct differences in Left- and Right-Sided Colon cancer. Mol Cancer Res. 2018;16(3):476–85.

    Article  CAS  PubMed  Google Scholar 

  50. Huang X, Liu J, Mo X, Liu H, Wei C, Huang L, et al. Systematic profiling of alternative splicing events and splicing factors in left- and right-sided colon cancer. Aging. 2019;11(19):8270–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jiang Y, Yan X, Liu K, Shi Y, Wang C, Hu J, et al. Discovering the molecular differences between right- and left-sided colon cancer using machine learning methods. BMC Cancer. 2020;20(1):1012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sun Y, Mironova V, Chen Y, Lundh EPF, Zhang Q, Cai Y, et al. Molecular pathway analysis indicates a distinct metabolic phenotype in women with Right-Sided Colon cancer. Transl Oncol. 2020;13(1):42–56.

    Article  CAS  PubMed  Google Scholar 

  53. Du K, Wang X, Li S, Ren J, Li R, Wang M, et al. Construction of a gut microbiota-gene-pathway network to reveal the molecular mechanisms underlying right- and left-sided colorectal cancer. FEMS Microbiol Lett. 2021;368:21–4.

    Google Scholar 

  54. Bayrak T, Cetin Z, Saygili EI, Ogul H. Identifying the tumor location-associated candidate genes in development of new drugs for colorectal cancer using machine-learning-based approach. Med Biol Eng Comput. 2022;60(10):2877–97.

    Article  PubMed  Google Scholar 

  55. Niu M, Chen C, Gao X, Guo Y, Zhang B, Wang X, et al. Comprehensive analysis of the differences between left- and right-side colorectal cancer and respective prognostic prediction. BMC Gastroenterol. 2022;22(1):482.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Zhang S, Xiao X, Yi Y, Wang X, Zhu L, Shen Y, et al. Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets. Signal Transduct Target Ther. 2024;9(1):149.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bradner JE, Hnisz D, Young RA. Transcriptional addiction in Cancer. Cell. 2017;168(4):629–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Vandereyken K, Sifrim A, Thienpont B, Voet T. Methods and applications for single-cell and Spatial multi-omics. Nat Rev Genet. 2023;24(8):494–515.

    Article  CAS  PubMed  Google Scholar 

  59. Kolisnik T, Sulit AK, Schmeier S, Frizelle F, Purcell R, Smith A, et al. Identifying important microbial and genomic biomarkers for differentiating right- versus left-sided colorectal cancer using random forest models. BMC Cancer. 2023;23(1):647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Xie B, Bai B, Xu Y, Liu Y, Lv Y, Gao X, et al. Tumor-suppressive function and mechanism of HOXB13 in right-sided colon cancer. Signal Transduct Target Ther. 2019;4:51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Liu XF, Olsson P, Wolfgang CD, Bera TK, Duray P, Lee B, et al. PRAC: A novel small nuclear protein that is specifically expressed in human prostate and colon. Prostate. 2001;47(2):125–31.

    Article  CAS  PubMed  Google Scholar 

  62. Zhang F, Ren CC, Liu L, Chen YN, Yang L, Zhang XA. HOXC6 gene Silencing inhibits epithelial-mesenchymal transition and cell viability through the TGF-beta/smad signaling pathway in cervical carcinoma cells. Cancer Cell Int. 2018;18:204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Huang H, Huo Z, Jiao J, Ji W, Huang J, Bian Z, et al. HOXC6 impacts epithelial-mesenchymal transition and the immune microenvironment through gene transcription in gliomas. Cancer Cell Int. 2022;22(1):170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ji M, Feng Q, He G, Yang L, Tang W, Lao X, et al. Silencing homeobox C6 inhibits colorectal cancer cell proliferation. Oncotarget. 2016;7(20):29216–27.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Qi L, Chen J, Zhou B, Xu K, Wang K, Fang Z, et al. HomeoboxC6 promotes metastasis by orchestrating the DKK1/Wnt/beta-catenin axis in right-sided colon cancer. Cell Death Dis. 2021;12(4):337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Qi L, Ye C, Zhang D, Bai R, Zheng S, Hu W, et al. The effects of Differentially-Expressed homeobox family genes on the prognosis and HOXC6 on immune microenvironment orchestration in colorectal Cancer. Front Immunol. 2021;12:781221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Baran B, Mert Ozupek N, Yerli Tetik N, Acar E, Bekcioglu O, Baskin Y. Difference between Left-Sided and Right-Sided colorectal cancer: A focused review of literature. Gastroenterol Res. 2018;11(4):264–73.

    Article  CAS  Google Scholar 

  68. Zhao J, Lin H, Huang K, Li S. Cancer-associated fibroblasts-derived extracellular vesicles carrying LncRNA SNHG3 facilitate colorectal cancer cell proliferation via the miR-34b-5p/HuR/HOXC6 axis. Cell Death Discov. 2022;8(1):346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Eneh S, Heikkinen S, Hartikainen JM, Kuopio T, Mecklin JP, Kosma VM, et al. MicroRNAs associated with biological pathways of Left- and Right-sided colorectal Cancer. Anticancer Res. 2020;40(7):3713–22.

    Article  CAS  PubMed  Google Scholar 

  70. De Nunzio V, Donghia R, Pesole PL, Coletta S, Calo N, Notarnicola M. Serum cytokine and MiRNA levels are differently expressed in Right- and Left-Sided Colon cancer. J Clin Med. 2023;12(18).

  71. Feng WQ, Zhang YC, Gao H, Li WC, Miao YM, Xu ZF et al. FOXD1 promotes chemotherapy resistance by enhancing cell stemness in colorectal cancer through beta–catenin nuclear localization. Oncol Rep. 2023;50(1).

  72. Han T, Lin J, Wang Y, Fan Q, Sun H, Tao Y, et al. Forkhead box D1 promotes proliferation and suppresses apoptosis via regulating polo-like kinase 2 in colorectal cancer. Biomed Pharmacother. 2018;103:1369–75.

    Article  CAS  PubMed  Google Scholar 

  73. Xie Y, Liu Y, Li Q, Chen J. Polo-like kinase 2 promotes chemoresistance and predicts limited survival benefit from adjuvant chemotherapy in colorectal cancer. Int J Oncol. 2018;52(5):1401–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lambert M, Jambon S, Depauw S, David-Cordonnier MH. Targeting transcription factors for Cancer treatment. Molecules. 2018;23(6).

  75. Hrudka J, Matej R, Nikov A, Tomyak I, Fiserova H, Jelinkova K, et al. Loss of SATB2 expression correlates with cytokeratin 7 and PD-L1 tumor cell positivity and aggressiveness in colorectal cancer. Sci Rep. 2022;12(1):19152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dum D, Ocokoljic A, Lennartz M, Hube-Magg C, Reiswich V, Hoflmayer D, et al. FABP1 expression in human tumors: a tissue microarray study on 17,071 tumors. Virchows Arch. 2022;481(6):945–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhao W, Pei Q, Zhu Y, Zhan D, Mao G, Wang M et al. The association of R-Loop binding proteins subtypes with CIN implicates therapeutic strategies in colorectal Cancer. Cancers (Basel). 2022;14(22).

  78. Cai H, Zheng D, Yao Y, Yang L, Huang X, Wang L. Roles of embryonic lethal abnormal Vision-Like RNA binding proteins in Cancer and beyond. Front Cell Dev Biol. 2022;10:847761.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kim Y, You JH, Ryu Y, Park G, Lee U, Moon HE, et al. ELAVL2 loss promotes aggressive mesenchymal transition in glioblastoma. NPJ Precis Oncol. 2024;8(1):79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Boonsanay V, Mosa MH, Looso M, Weichenhan D, Ceteci F, Pudelko L, et al. Loss of SUV420H2-Dependent chromatin compaction drives Right-Sided Colon cancer progression. Gastroenterology. 2023;164(2):214–27.

    Article  CAS  PubMed  Google Scholar 

  81. Dum D, Kromm D, Lennartz M, De Wispelaere N, Buscheck F, Luebke AM, et al. SATB2 expression in human tumors: A tissue microarray study on more than 15 000 tumors. Arch Pathol Lab Med. 2023;147(4):451–64.

    Article  CAS  PubMed  Google Scholar 

  82. Brown RE, Short SP, Williams CS. Colorectal Cancer and metabolism. Curr Colorectal Cancer Rep. 2018;14(6):226–41.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Zhang J, Zou S, Fang L. Metabolic reprogramming in colorectal cancer: regulatory networks and therapy. Cell Biosci. 2023;13(1):25.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ludikhuize MC, Gevers S, Nguyen NTB, Meerlo M, Roudbari SKS, Gulersonmez MC, et al. Rewiring glucose metabolism improves 5-FU efficacy in p53-deficient/KRAS(G12D) glycolytic colorectal tumors. Commun Biol. 2022;5(1):1159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Marx C, Sonnemann J, Maddocks ODK, Marx-Blumel L, Beyer M, Hoelzer D, et al. Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress. Cancer Metab. 2022;10(1):10.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Refaat B, Zekri J, Aslam A, Ahmad J, Baghdadi MA, Meliti A, et al. Profiling activins and follistatin in colorectal Cancer according to clinical stage, tumour sidedness and Smad4 status. Pathol Oncol Res. 2021;27:1610032.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Lawrie LC, Dundas SR, Curran S, Murray GI. Liver fatty acid binding protein expression in colorectal neoplasia. Br J Cancer. 2004;90(10):1955–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rodriguez Sawicki L, Bottasso Arias NM, Scaglia N, Falomir Lockhart LJ, Franchini GR, Storch J, et al. FABP1 knockdown in human enterocytes impairs proliferation and alters lipid metabolism. Biochim Biophys Acta Mol Cell Biol Lipids. 2017;1862(12):1587–94.

    Article  CAS  PubMed  Google Scholar 

  89. Han J, Zuo J, Zhang X, Wang L, Li D, Wang Y, et al. TRIM29 is differentially expressed in colorectal cancers of different primary locations and affects survival by regulating tumor immunity based on retrospective study and bioinformatics analysis. J Gastrointest Oncol. 2022;13(3):1132–51.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Han J, Zhao Z, Zhang N, Yang Y, Ma L, Feng L, et al. Transcriptional dysregulation of TRIM29 promotes colorectal cancer carcinogenesis via pyruvate kinase-mediated glucose metabolism. Aging. 2021;13(4):5034–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sun L, Wang D, Chen Z, Zhu X. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5. Open Life Sci. 2023;18(1):20220711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Huang W, Hu X, He X, Pan D, Huang Z, Gu Z, et al. TRIM29 facilitates gemcitabine resistance via MEK/ERK pathway and is modulated by circRPS29/miR-770-5p axis in PDAC. Drug Resist Updat. 2024;74:101079.

    Article  CAS  PubMed  Google Scholar 

  93. Masuda Y, Takahashi H, Sato S, Tomomori-Sato C, Saraf A, Washburn MP, et al. TRIM29 regulates the assembly of DNA repair proteins into damaged chromatin. Nat Commun. 2015;6:7299.

    Article  CAS  PubMed  Google Scholar 

  94. Lei G, Liu S, Yang X, He C. TRIM29 reverses oxaliplatin resistance of P53 mutant Colon cancer cell. Can J Gastroenterol Hepatol. 2021;2021:8870907.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Yuan Z, Villagra A, Peng L, Coppola D, Glozak M, Sotomayor EM, et al. The ATDC (TRIM29) protein binds p53 and antagonizes p53-mediated functions. Mol Cell Biol. 2010;30(12):3004–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Figueiredo JC, Passarelli MN, Wei W, Ahnen DJ, Morris JS, Corley L, et al. Proliferation, apoptosis and their regulatory protein expression in colorectal adenomas and serrated lesions. PLoS ONE. 2021;16(11):e0258878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhan Y, Zheng L, Liu J, Hu D, Wang J, Liu K et al. PLA2G4A promotes right-sided colorectal cancer progression by inducing CD39 + gammadelta Treg polarization. JCI Insight. 2021;6(16).

  98. Abe Y, Nakayama Y, Katsuki T, Inoue Y, Minagawa N, Torigoe T, et al. The prognostic significance of the expression of monocarboxylate transporter 4 in patients with right- or left-sided colorectal cancer. Asia Pac J Clin Oncol. 2019;15(2):e49–55.

    Article  PubMed  Google Scholar 

  99. Kumbrink J, Li P, Pok-Udvari A, Klauschen F, Kirchner T, Jung A. p130Cas is correlated with EREG expression and a prognostic factor depending on colorectal Cancer stage and localization reducing FOLFIRI efficacy. Int J Mol Sci. 2021;22(22).

  100. Dong W, Li N, Pei X, Wu X. Differential expression of DUSP2 in left- and right-sided colon cancer is associated with poor prognosis in colorectal cancer. Oncol Lett. 2018;15(4):4207–14.

    PubMed  PubMed Central  Google Scholar 

  101. Song J, Yang J, Lin R, Cai X, Zheng L, Chen Y. Molecular heterogeneity of guanine nucleotide binding-protein gamma subunit 4 in left- and right-sided colon cancer. Oncol Lett. 2020;20(6):334.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Parikh AA, Fan F, Liu WB, Ahmad SA, Stoeltzing O, Reinmuth N, et al. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol. 2004;164(6):2139–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang N, Zhang R, Zou K, Yu W, Guo W, Gao Y, et al. Keratin 23 promotes telomerase reverse transcriptase expression and human colorectal cancer growth. Cell Death Dis. 2017;8(7):e2961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Deng Y, Zheng X, Zhang Y, Xu M, Ye C, Lin M, et al. High SPRR1A expression is associated with poor survival in patients with colon cancer. Oncol Lett. 2020;19(5):3417–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Jin L, Chun J, Pan C, Li D, Lin R, Alesi GN, et al. MAST1 drives cisplatin resistance in human cancers by rewiring cRaf-Independent MEK activation. Cancer Cell. 2018;34(2):315–30. e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Corrales L, Hipp S, Martin K, Sabarth N, Tirapu I, Fuchs K, et al. LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager. Front Immunol. 2022;13:1008764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Giordano G, Parcesepe P, D’Andrea MR, Coppola L, Di Raimo T, Remo A, et al. JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer. J Exp Clin Cancer Res. 2019;38(1):28.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Matsuyama T, Ishikawa T, Mogushi K, Yoshida T, Iida S, Uetake H, et al. MUC12 mRNA expression is an independent marker of prognosis in stage II and stage III colorectal cancer. Int J Cancer. 2010;127(10):2292–9.

    Article  CAS  PubMed  Google Scholar 

  109. Kleeff J, Huang Y, Mok SC, Zimmermann A, Friess H, Buchler MW. Down-regulation of DOC-2 in colorectal cancer points to its role as a tumor suppressor in this malignancy. Dis Colon Rectum. 2002;45(9):1242–8.

    Article  PubMed  Google Scholar 

  110. Sustic I, Racetin A, Vukojevic K, Benzon B, Tonkic A, Sundov Z et al. Expression pattern of DAB adaptor protein 2 in Left- and Right-Side colorectal carcinoma. Genes (Basel). 2023;14(7).

  111. Figliuolo da Paz V, Ghishan FK, Kiela PR. Emerging roles of disabled homolog 2 (DAB2) in immune regulation. Front Immunol. 2020;11:580302.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Zhang Y, Zhong Z, Li M, Chen J, Lin T, Sun J, et al. The roles and prognostic significance of ABI1-TSV-11 expression in patients with left-sided colorectal cancer. Sci Rep. 2021;11(1):10734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ma B, Ueda H, Okamoto K, Bando M, Fujimoto S, Okada Y, et al. TIMP1 promotes cell proliferation and invasion capability of right-sided colon cancers via the FAK/Akt signaling pathway. Cancer Sci. 2022;113(12):4244–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hu H, Wu D, Liu X, Yu H, Xu J, Cai W, et al. SPARCL1 exhibits different expressions in left- and right-sided colon cancer and is downregulated via DNA methylation. Epigenomics. 2021;13(16):1269–82.

    Article  CAS  PubMed  Google Scholar 

  115. Gelsomino F, Barbolini M, Spallanzani A, Pugliese G, Cascinu S. The evolving role of microsatellite instability in colorectal cancer: A review. Cancer Treat Rev. 2016;51:19–26.

    Article  CAS  PubMed  Google Scholar 

  116. Zhang L, Zhao Y, Dai Y, Cheng JN, Gong Z, Feng Y, et al. Immune landscape of colorectal Cancer tumor microenvironment from different primary tumor location. Front Immunol. 2018;9:1578.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Liu D, Li C, Deng Z, Luo N, Li W, Hu W, et al. Multi-omics analysis reveals the landscape of tumor microenvironments in left-sided and right-sided colon cancer. Front Med (Lausanne). 2024;11:1403171.

    Article  PubMed  Google Scholar 

  118. Liu B, Li S, Cheng Y, Song P, Xu M, Li Z, et al. Distinctive multicellular immunosuppressive hubs confer different intervention strategies for left- and right-sided colon cancers. Cell Rep Med. 2024;5(6):101589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Talhouni S, Fadhil W, Mongan NP, Field L, Hunter K, Makhsous S, et al. Activated tissue resident memory T-cells (CD8 + CD103 + CD39+) uniquely predict survival in left sided immune-hot colorectal cancers. Front Immunol. 2023;14:1057292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Guo D, Li X, Xie A, Cao Q, Zhang J, Zhang F, et al. Differences in oncological outcomes and inflammatory biomarkers between right-sided and left-sided stage I-III colorectal adenocarcinoma. J Clin Lab Anal. 2020;34(4):e23132.

    Article  CAS  PubMed  Google Scholar 

  121. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011;241(1):260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Takasu C, Nishi M, Yoshikawa K, Tokunaga T, Kashihara H, Yoshimoto T, et al. Impact of sidedness of colorectal cancer on tumor immunity. PLoS ONE. 2020;15(10):e0240408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lu Y, Wang X, Gu J, Lu H, Zhang F, Li X, et al. iTreg induced from CD39(+) Naive T cells demonstrate enhanced proliferate and suppressive ability. Int Immunopharmacol. 2015;28(2):925–30.

    Article  CAS  PubMed  Google Scholar 

  124. Liu X, Xu X, Wu Z, Shan Q, Wang Z, Wu Z, et al. Integrated single-cell RNA-seq analysis identifies immune heterogeneity associated with KRAS/TP53 mutation status and tumor-sideness in colorectal cancers. Front Immunol. 2022;13:961350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kobayashi H, Gieniec KA, Lannagan TRM, Wang T, Asai N, Mizutani Y, et al. The origin and contribution of Cancer-Associated fibroblasts in colorectal carcinogenesis. Gastroenterology. 2022;162(3):890–906.

    Article  CAS  PubMed  Google Scholar 

  126. Ahmad Zawawi SS, Musa M. Dynamic Co-Evolution of Cancer Cells and Cancer-Associated Fibroblasts: Role in Right- and Left-Sided Colon Cancer Progression and Its Clinical Relevance. Biology (Basel). 2022;11(7).

  127. DeDecker L, Coppedge B, Avelar-Barragan J, Karnes W, Whiteson K. Microbiome distinctions between the CRC carcinogenic pathways. Gut Microbes. 2021;13(1):1854641.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Aljama S, Lago EP, Zafra O, Sierra J, Simon D, Santos C, et al. Dichotomous colorectal cancer behaviour. Crit Rev Oncol Hematol. 2023;189:104067.

    Article  PubMed  Google Scholar 

  129. Jin M, Shang F, Wu J, Fan Q, Chen C, Fan J, et al. Tumor-Associated microbiota in proximal and distal colorectal Cancer and their relationships with clinical outcomes. Front Microbiol. 2021;12:727937.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Miyake T, Mori H, Yasukawa D, Hexun Z, Maehira H, Ueki T, et al. The comparison of fecal microbiota in Left-Side and Right-Side human colorectal Cancer. Eur Surg Res. 2021;62(4):248–54.

    Article  CAS  PubMed  Google Scholar 

  131. Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal Cancer by modulating autophagy. Cell. 2017;170(3):548–63. e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang S, Yang Y, Weng W, Guo B, Cai G, Ma Y, et al. Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer. J Exp Clin Cancer Res. 2019;38(1):14.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Jiang SS, Xie YL, Xiao XY, Kang ZR, Lin XL, Zhang L, et al. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer. Cell Host Microbe. 2023;31(5):781–97. e9.

    Article  CAS  PubMed  Google Scholar 

  134. Hou XY, Zhang P, Du HZ, Gao YQ, Sun RQ, Qin SY, et al. Prevotella contributes to individual response of FOLFOX in colon cancer. Clin Transl Med. 2021;11(9):e512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Lo CH, Wu DC, Jao SW, Wu CC, Lin CY, Chuang CH, et al. Enrichment of Prevotella intermedia in human colorectal cancer and its additive effects with Fusobacterium nucleatum on the malignant transformation of colorectal adenomas. J Biomed Sci. 2022;29(1):88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Hou X, Zhang P, Du H, Chu W, Sun R, Qin S, et al. Akkermansia Muciniphila potentiates the antitumor efficacy of FOLFOX in Colon cancer. Front Pharmacol. 2021;12:725583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Suga D, Mizutani H, Fukui S, Kobayashi M, Shimada Y, Nakazawa Y, et al. The gut microbiota composition in patients with right- and left-sided colorectal cancer and after curative colectomy, as analyzed by 16S rRNA gene amplicon sequencing. BMC Gastroenterol. 2022;22(1):313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Xu Y, Zhao J, Ma Y, Liu J, Cui Y, Yuan Y, et al. The Microbiome types of colorectal tissue are potentially associated with the prognosis of patients with colorectal cancer. Front Microbiol. 2023;14:1100873.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Fan S, Zhou L, Zhang W, Wang D, Tang D. Role of imbalanced gut microbiota in promoting CRC metastasis: from theory to clinical application. Cell Commun Signal. 2024;22(1):232.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Wang J, Ghosh D, Maniruzzaman M. Using Bugs as drugs: administration of bacteria-related microbes to fight cancer. Adv Drug Deliv Rev. 2023;197:114825.

    Article  CAS  PubMed  Google Scholar 

  141. Phipps O, Quraishi MN, Dickson EA, Steed H, Kumar A, Acheson AG et al. Differences in the On- and Off-Tumor microbiota between Right- and Left-Sided colorectal Cancer. Microorganisms. 2021;9(5).

  142. Imai H, Saijo K, Komine K, Yoshida Y, Sasaki K, Suzuki A, et al. Antibiotics improve the treatment efficacy of Oxaliplatin-Based but not Irinotecan-Based therapy in advanced colorectal Cancer patients. J Oncol. 2020;2020:1701326.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Roy S, Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer. 2017;17(5):271–85.

    Article  CAS  PubMed  Google Scholar 

  144. Zhao LY, Mei JX, Yu G, Lei L, Zhang WH, Liu K, et al. Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications. Signal Transduct Target Ther. 2023;8(1):201.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Figures were generated using https://www.biorender.com.

Funding

This work was supported by grants from the National Health and Medical Research Council of Australia, projects 1188689, 2021181 and in part by “Lets Beat Bowel Cancer” a benevolent fundraising and public awareness foundation that has had no part in the design, conduct, outcomes or drafting of the manuscript.

Author information

Authors and Affiliations

  1. Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia

    Harrison J. Boka, Rebekah M. Engel & Helen E. Abud

  2. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia

    Harrison J. Boka, Rebekah M. Engel & Helen E. Abud

  3. Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia

    Harrison J. Boka, Rebekah M. Engel, Christine Georges, Paul J. McMurrick & Helen E. Abud

Authors
  1. Harrison J. Boka
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Rebekah M. Engel
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Christine Georges
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Paul J. McMurrick
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Helen E. Abud
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

HB, RE and HA developed the idea and structure of the review, conducted literature searches, data analysis and authored the manuscript. CG and PJM completed data analysis. HB generated the tables and figures. All authors critically revised the final manuscript.

Corresponding author

Correspondence to Helen E. Abud.

Ethics declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boka, H.J., Engel, R.M., Georges, C. et al. Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer. Mol Cancer 24, 130 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12943-025-02327-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12943-025-02327-5

Keywords

Molecular Cancer

ISSN: 1476-4598