Review

Authors: Inés Mármol, Cristina Sánchez-de-Diego, Alberto Pradilla Dieste...

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%-5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include spp, and enteropathogenic . CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53), and mutations; in particular, genes such as c-MYC, , , , , and can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects.

Topics: Colorectal Neoplasms; Genetic Predisposition to Disease; Humans; Neoplasm Staging; Risk Factors; Signal Transduction

PubMed: 28106826
DOI: 10.3390/ijms18010197

Review

Authors: Adrià Cañellas-Socias, Elena Sancho, Eduard Batlle...

Despite extensive research and improvements in understanding colorectal cancer (CRC), its metastatic form continues to pose a substantial challenge, primarily owing to limited therapeutic options and a poor prognosis. This Review addresses the emerging focus on metastatic CRC (mCRC), which has historically been under-studied compared with primary CRC despite its lethality. We delve into two crucial aspects: the molecular and cellular determinants facilitating CRC metastasis and the principles guiding the evolution of metastatic disease. Initially, we examine the genetic alterations integral to CRC metastasis, connecting them to clinically marked characteristics of advanced CRC. Subsequently, we scrutinize the role of cellular heterogeneity and plasticity in metastatic spread and therapy resistance. Finally, we explore how the tumour microenvironment influences metastatic disease, emphasizing the effect of stromal gene programmes and the immune context. The ongoing research in these fields holds immense importance, as its future implications are projected to revolutionize the treatment of patients with mCRC, hopefully offering a promising outlook for their survival.

Topics: Humans; Colorectal Neoplasms; Tumor Microenvironment; Neoplasm Metastasis

PubMed: 38806657
DOI: 10.1038/s41575-024-00934-z

Review

Authors: Shu-Chang Ma, Jia-Qi Zhang, Tian-Hua Yan...

Colorectal cancer (CRC) is a common gastrointestinal malignancy with high morbidity and fatality. Chemotherapy, as traditional therapy for CRC, has exerted well antitumor effect and greatly improved the survival of CRC patients. Nevertheless, chemoresistance is one of the major problems during chemotherapy for CRC and significantly limits the efficacy of the treatment and influences the prognosis of patients. To overcome chemoresistance in CRC, many strategies are being investigated. Here, we review the common and novel measures to combat the resistance, including drug repurposing (nonsteroidal anti-inflammatory drugs, metformin, dichloroacetate, enalapril, ivermectin, bazedoxifene, melatonin, and S-adenosylmethionine), gene therapy (ribozymes, RNAi, CRISPR/Cas9, epigenetic therapy, antisense oligonucleotides, and noncoding RNAs), protein inhibitor (EFGR inhibitor, S1PR2 inhibitor, and DNA methyltransferase inhibitor), natural herbal compounds (polyphenols, terpenoids, quinones, alkaloids, and sterols), new drug delivery system (nanocarriers, liposomes, exosomes, and hydrogels), and combination therapy. These common or novel strategies for the reversal of chemoresistance promise to improve the treatment of CRC.

Topics: Humans; MicroRNAs; Drug Resistance, Neoplasm; Colorectal Neoplasms; RNA Interference; Prognosis; Cell Line, Tumor

PubMed: 36645225
DOI: 10.1002/cam4.5594

Review

Authors: Shigeyoshi Kijima, Takahiro Sasaki, Koichi Nagata...

Imaging studies are a major component in the evaluation of patients for the screening, staging and surveillance of colorectal cancer. This review presents commonly encountered findings in the diagnosis and staging of patients with colorectal cancer using computed tomography (CT) colonography, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT colonography. CT colonography provides important information for the preoperative assessment of T staging. Wall deformities are associated with muscular or subserosal invasion. Lymph node metastases from colorectal cancer often present with calcifications. CT is superior to detect calcified metastases. Three-dimensional CT to image the vascular anatomy facilitates laparoscopic surgery. T staging of rectal cancer by MRI is an established modality because MRI can diagnose rectal wall laminar structure. N staging in patients with colorectal cancer is still challenging using any imaging modality. MRI is more accurate than CT for the evaluation of liver metastases. PET/CT colonography is valuable in the evaluation of extra-colonic and hepatic disease. PET/CT colonography is useful for obstructing colorectal cancers that cannot be traversed colonoscopically. PET/CT colonography is able to localize synchronous colon cancers proximal to the obstruction precisely. However, there is no definite evidence to support the routine clinical use of PET/CT colonography.

Topics: Colonography, Computed Tomographic; Colorectal Neoplasms; Humans; Lymphatic Metastasis; Magnetic Resonance Imaging; Multimodal Imaging; Neoplasm Invasiveness; Neoplasm Staging; Positron-Emission Tomography; Predictive Value of Tests

PubMed: 25493009
DOI: 10.3748/wjg.v20.i45.16964

Review

Authors: Hui Wang, Tian Tian, Jinhua Zhang...

Colorectal cancer (CRC) is a malignant tumor in the digestive system whose incidence and mortality is high-ranking among tumors worldwide. The initiation and progression of CRC is a complex process involving genetic alterations in cancer cells and multiple factors from the surrounding tumor cell microenvironment. As accumulating evidence has shown, tumor-associated macrophages (TAMs)-as abundant and active infiltrated inflammatory cells in the tumor microenvironment (TME)-play a crucial role in CRC. This review focuses on the different mechanisms of TAM in CRC, including switching of phenotypical subtypes; promoting tumor proliferation, invasion, and migration; facilitating angiogenesis; mediating immunosuppression; regulating metabolism; and interacting with the microbiota. Although controversy remains in clinical evidence regarding the role of TAMs in CRC, clarifying their significance in therapy and the prognosis of CRC may shed new light on the optimization of TAM-centered approaches in clinical care.

Topics: Animals; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Disease Management; Humans; Immunotherapy; Neoplasm Invasiveness; Prognosis; Tumor-Associated Macrophages

PubMed: 34445193
DOI: 10.3390/ijms22168470

Review

Authors: Leandro Kasuki, Bernardo Maia, Mônica R Gadelha...

Acromegaly is a systemic disease caused by excessive inappropriate secretion of GH and IGF-I levels, resulting in many systemic complications, including cardiovascular, respiratory, metabolic diseases, and a possible increased risk of some neoplasias. Although many studies on acromegaly and cancer remain uncertain, most data indicate that colorectal cancer (CRC) incidence is increased in this population. The exact mechanism involved in the role of GH-IGF-I axis in CRC has not been fully explained, yet it is associated with local and circulating effects of GH and IGF-I on the colon, promoting angiogenesis, cell proliferation, risk of mutation, inhibition of tumor-suppressor genes and apoptosis, thus facilitating a tumor microenvironment. Nevertheless, population-based studies present controversial findings on CRC incidence and mortality. All worldwide guidelines and expert consensuses agree with the need for colonoscopic screening and surveillance in acromegaly, although there is no consensus regarding the best period to do this. This review aims to analyze the existing data on CRC and acromegaly, exploring its pathophysiology, epidemiological studies and their limitations, colonic polyp characteristics, overall cancer and CRC incidences and mortality, risk factors for colon cancer pathophysiology, and recommendation guideline aspects.

Topics: Acromegaly; Cell Proliferation; Colorectal Neoplasms; Humans; Insulin-Like Growth Factor I; Tumor Microenvironment

PubMed: 35795151
DOI: 10.3389/fendo.2022.924952

Authors: Yunho Jung

Topics: Adenoma; Colorectal Neoplasms; Female; Humans; Menarche; Risk Factors

PubMed: 31466433
DOI: 10.3904/kjim.2019.261

Review

Authors: Emilie Picard, Chris P Verschoor, Grace W Ma...

Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.

Topics: Antigens, Neoplasm; Cancer Vaccines; Colorectal Neoplasms; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Immunotherapy, Adoptive; Microsatellite Instability; Prognosis; Tumor Escape

PubMed: 32210966
DOI: 10.3389/fimmu.2020.00369

Authors: Chuangen Li, Yong Wang, Dabin Liu...

OBJECTIVE

Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis.

DESIGN

Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses.

RESULTS

SQLE messenger RNA and protein expression was upregulated in CRC (p<0.01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p<0.01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth.

CONCLUSION

This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.

Topics: Animals; Azoxymethane; Bile Acids and Salts; Carcinogenesis; Cell Proliferation; Cholesterol; Colorectal Neoplasms; Dysbiosis; Fluorouracil; Mice; Occludin; Oxaliplatin; RNA, Messenger; Squalene Monooxygenase; Terbinafine

PubMed: 35232776
DOI: 10.1136/gutjnl-2021-325851

Meta-Analysis

Authors: Yun Tian, Jirong Wang, Ying Ye...

To investigate the relationship of Apolipoprotein E (APOE) gene polymorphism to colorectal neoplasia (CRN), we performed a systematic review and meta-analysis. Eligible studies were identified through a systematic literature review from PubMed, EMBASE, and the Science Citation Index up to February 2014. A combined analysis was performed, followed by a subgroup analyses stratified by the study design. We used data collected from 8 prospective studies involving respectively a total of 9243 participants and 4310 CRN cases which including 438 patients with colorectal adenoma (CRA), and 3873 patients with colorectal carcinoma (CRC). The pooled data from this meta-analysis indicated there was no significant association between APOE polymorphism and CRN (ε2: P = 0.51, OR 1.04 95% CI 0.93 to 1.16; ε4: P = 0.72, OR 0.98 95% CI 0.90 to 1.07). Interestingly, subgroup analysis demonstrated there was a significant decreased risk for proximal CRN in patients with APOE ε4 (P = 0.0007, OR 0.52 95% CI 0.35 to 0.76). Data showed no significant association between APOE genotype and overall CRN. However, compared with those carry APOE ε3 alleles, persons with APOE ε4 genotype have significant decreased risk suffering from proximal CRN but not from distal CRN.

Topics: Apolipoproteins E; Colorectal Neoplasms; Gene Frequency; Genotype; Humans; Odds Ratio; Polymorphism, Genetic

PubMed: 25029444
DOI: 10.1371/journal.pone.0102477