Colorectal Cancer Research Articles

Literature Review on Stages of Colorectal Cancer

Colorectal cancer, primarily originating from polyps in the colon or rectum, represents a significant health challenge due to its potential progression to malignancy. Polyps, abnormal tissue growths in the inner lining of the colon or rectum, often start as benign adenomas. Over time, these adenomas may undergo cellular mutations, transforming into cancerous tumors. Early detection and removal of polyps during screening significantly reduce the likelihood of cancer development. If left untreated, colorectal cancer can invade deeper layers of the colon wall, metastasize to nearby lymph nodes, and spread to distant organs, commonly the liver, peritoneum, or lungs. Colon cancer typically originates in the mucosa, the innermost lining of the colon, and progresses through the tissue and muscle layers over a span of approximately 10 years. The anatomy of the colon and rectum, consisting of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, plays a critical role in understanding the disease's progression. Advances in screening methods and treatments have significantly improved outcomes, emphasizing the importance of early intervention in reducing colorectal cancer mortality.

MSH2-Mutated Lynch Syndrome With 9 Synchronous Colon and Rectum Adenocarcinomas: An Extremely Rare Case Report

Synchronous colorectal carcinoma is having more than 1 primary carcinoma detected in a single patient at the same time or within 6 months of tumor diagnosis. Metachronous colorectal carcinoma is the presence of more than 1 primary carcinoma detected consecutively in a single person after a set time interval. Patients with Lynch syndrome and Muir-Torre syndrome (a subset of Lynch syndrome) inherit a germline mutation in 1 of the mismatch repair (MMR) genes. Patients with synchronous colorectal carcinoma have a higher proportion of MMR-mutated cancers than patients with solitary colorectal carcinoma. Most studies in the literature indicate that patients with synchronous colorectal cancers typically have only 2 carcinomas. However, there have been reports of a single patient having up to 6 synchronous carcinomas in the large intestine. This report discusses a patient with 9 simultaneous colorectal cancers at the initial diagnosis, along with a history of bladder cancer, sebaceous adenoma, and duodenal adenoma, associated with a germline mutS homolog 2 ( MSH2) mutation. Additionally, the report explores various aspects of having synchronous colorectal cancers. More studies are needed to clarify the clinicopathologic and molecular landscape of these rare tumors and identify the best management and treatment strategies for these patients.

Late-line options for patients with metastatic colorectal cancer: a review and evidence-based algorithm

Late-line options for patients with metastatic colorectal cancer: a review and evidence-based algorithm

Effectiveness and Safety of Regorafenib and TAS-102 in Patients with Metastatic Colorectal Cancer: A Nationwide Population-Based Study in Taiwan

Effectiveness and Safety of Regorafenib and TAS-102 in Patients with Metastatic Colorectal Cancer: A Nationwide Population-Based Study in Taiwan

In-depth analysis of lymph node metastasis-related sialylated protein profiling and their clinical and biological significance in colorectal cancer using mass spectrometry and multi-omics technologies

In-depth analysis of lymph node metastasis-related sialylated protein profiling and their clinical and biological significance in colorectal cancer using mass spectrometry and multi-omics technologies

PD-L1 promotes tumor metastasis by regulating the infiltration of FGFBP2(+)Tm cells in colorectal cancer

PD-L1 promotes tumor metastasis by regulating the infiltration of FGFBP2(+)Tm cells in colorectal cancer

Multi-omics analysis reveals the role of the autophagy-related gene AGT in chemotherapy resistance in colorectal cancer and the therapeutic potential of its inhibitors

Multi-omics analysis reveals the role of the autophagy-related gene AGT in chemotherapy resistance in colorectal cancer and the therapeutic potential of its inhibitors

Third- or Further-Line Treatment in Patients with MSS Type Metastatic Colorectal Cancer

Third- or Further-Line Treatment in Patients with MSS Type Metastatic Colorectal Cancer

Is the Multitarget Stool DNA Test Just a Better “FIT” for Colorectal Cancer Screening?

Is the Multitarget Stool DNA Test Just a Better “FIT” for Colorectal Cancer Screening?

The Effect of Vitamin D Supplementation on Quality of Life in Stage II–III Colorectal Cancer Patients Undergoing Adjuvant Chemotherapy: A Single-Blind, Randomized Controlled Trial

The Effect of Vitamin D Supplementation on Quality of Life in Stage II–III Colorectal Cancer Patients Undergoing Adjuvant Chemotherapy: A Single-Blind, Randomized Controlled Trial

Comprehensive profiling of extrachromosomal circular DNAs in colorectal cancer progression

Comprehensive profiling of extrachromosomal circular DNAs in colorectal cancer progression

Next-Generation Multitarget Stool DNA vs Fecal Immunochemical Test in Colorectal Cancer Screening

This diagnostic study compares the specificity and sensitivity of comercial fecal immunochemical tests with a multitarget stool DNA test.

Predictors of Recurrence After Curative Surgery for Stage I Colon Cancer: Retrospective Cohort Analysis of the Italian Society of Surgical Oncology Colorectal Cancer Network Collaborative Group

Objective: The aim of this study is to provide solid evidence to update the management of stage I colon cancer (CC) after surgery. Background: Given the low risk of recurrence of stage I CC, some international guidelines do not recommend intensive follow-up after surgery. However, data on the actual incidence, risk factors, and site of recurrences are scarce. Methods: This is a retrospective multicenter cohort study considering patients who underwent surgery at 25 Italian centers between 2010 and 2019, with a minimum follow-up of 24 months. A total of 1883 consecutive adult patients with stage I CC treated with curative surgery were considered, and 1611 fulfilled the inclusion criteria. The primary outcome was the rate of recurrence. Secondary outcomes included survival and risk factors for recurrence. Results: Eighty patients developed cancer recurrence (5.0%), of which 90% was systemic relapse. The event was more frequent in pT2 (6.0% vs 3.2%, P = 0.013), male patients (6.1% vs 3.6%, P = 0.021), in the presence of lymphovascular invasion (7.2% vs 3.6%, P = 0.01), and in cases of partial resection (11.1% vs 4.6%, P = 0.011). Also, preoperative carcinoembryonic antigen (P = 0.007) and tumor diameter (P < 0.001) were higher in the group who relapsed. Most patients had isolated cancer recurrence (90%). Recurrences peaked between 10 and 18 months after surgery and declined over time. Adjusted Cox regression analysis identified tumor diameter, carcinoembryonic antigen level, lymphovascular invasion, male gender, and less than 12 analyzed lymph nodes as significant risk factors for worse recurrence-free survival. Conclusions: This study showed that a not negligible rate of stage I CC recur after curative surgery. Most relapses occur at a single site within the first 3 years after surgery. This evidence could be used to optimize postoperative follow-up.

Development, characterization, and assessment of PLAROsomal vesicular system of curcumin for enhanced stability and therapeutic efficacy

Abstract Background Curcumin (CUR) is a natural polyphenol and one of the key phytoconstituents found in the rhizomes of Curcuma Longa. It exhibits various pharmacological properties, encompassing antioxidant, anticancer effects, antiseptic, and anti-inflammatory, among several others. A significant drawback of using CUR is its limited bioavailability, which primarily depends on gut microorganisms responsible for converting it into its bioavailable form. Therefore, the contemporary study intended to formulate a novel PLAROsomal vesicular delivery of CUR, i.e., CUR-PLAROsomes employing a design of experiments approach to examine the influence of various process parameters, such as particle size and drug percentage release. Result The prepared CUR-PLAROsomes were characterized for their physicochemical properties using various hyphenated tools. The CUR-PLAROsomes exhibited sizes ranging from 40 to 300 nm, and the optimized batch demonstrated a drug entrapment of 86.38 ± 0.22%. In-vitro anticancer studies were conducted using human colorectal adenocarcinoma cells (COLO320DM) and human breast adenocarcinoma (MCF-7). CUR-PLAROsomes exhibited significant in-vivo anti-inflammatory potential against carrageenan-induced paw edema. CUR-PLAROsomes were more potent against COLO320DM and MCF-7 cell lines, even at lower concentrations, than pure CUR. Conclusion Furthermore, based on the observations, it exhibits potential as an anti-inflammatory agent, suggesting that PLAROsomes are an effective vesicular drug delivery system. Highlights Newly introduced PLARosome is a next generation of Liposomes which have gain popularity owing to its better adaptability to overcome leakage problem of vesicular drug delivery system. This is the pioneer attempt to prepare Curcumin-loaded PLARosome as an anti-cancer and anti-inflammatory activity. Nano size of the PLAROsomes may contribute to enhance the efficacy of Curcumin as a target specific drug delivery system. Site specific delivery of phytoconstituents is possible by use of PLAROsomes as a novel drug delivery system. Graphical abstract

IL-2/anti-IL-2 antibody complexes augment immune responses to therapeutic cancer vaccines

One driver of the high failure rates of clinical trials for therapeutic cancer vaccines is likely the inability to sufficiently engage conventional dendritic cells (cDCs), the antigen-presenting cell (APC) subset that is specialized in priming antitumor T cells. Here, we demonstrate that, relative to vaccination with an injectable mesoporous silica rod (MPS) vaccine alone (Vax), combining MPS vaccines with CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2cx) drives ~3-fold expansion of cDCs at the vaccination sites, vaccine-draining lymph nodes, and spleens of treated mice. Furthermore, relative to Vax alone, Vax+IL-2cx led to a ~3-fold increase in the numbers of CD8 + T cells and ~15-fold increase in the numbers of NK cells at the vaccination site. Notably, with both the model protein antigen OVA as well as various peptide neoantigens, Vax+IL-2cx induced ~5 to 30-fold greater numbers of circulating antigen-specific CD8 + T cells relative to Vax alone. We further demonstrate that Vax+IL-2cx leads to significantly improved efficacy in the MC38 colon carcinoma model relative to either monotherapy alone, driving complete regressions in 50% of mice in a cDC-dependent manner. Relative to vaccine alone, Vax+IL-2cx led to comparable numbers of CD8 + T cells, but markedly greater numbers of NK cells and activated cDCs in the B16F10 melanoma tumor microenvironment post-therapy. Taken together, these findings suggest that the administration of factors that engage both the cDC-CD8 + T cell and cDC-NK cell axes can boost the potency of therapeutic cancer vaccines.

Abstract B018: Multifaceted pro-metastatic role of IL-17 signaling in modulating the tumor microenvironment of colorectal cancer

Abstract Colorectal cancer (CRC) ranks second in mortality and advanced CRCs are resistant to current immunotherapies and prone to metastasis, which necessitates research into enhancing innate and adaptive anti-cancer immune responses. Chronic inflammation mediated by cytokines like IL6 and notably, IL17 activates the oncogenic pathways in cancer cells, promoting sporadic and inflammatory CRC. What is unknown, is the ability of cytokines to control tumor microenvironment (TME) via cell type specific mechanisms to increase cancer progression, metastasis and/or therapy resistance. Increased levels of IL17A in CRC portends poor prognosis indicating its potential involvement into metastasis. However, the role of IL17 signaling in TME in the process of CRC progression and metastasis remains enigmatic. We utilized different models of CRC progression and metastasis, as well as variety of genetic mice models and therapeutic interventions. First, using a model of colitis-associated cancer we found that “late” IL17A neutralization decreases tumor burden, possibly acting through regulation of ferroptosis, NK cells mediated cytotoxicity, as well as myeloid cells and chemokine network essential for the control of immunosuppressive TME. Next, models of CRC metastasis, including those based on MC38 cells and APTAK cancerous organoids, showed that IL17A neutralization reduces metastasis growth. Also, FACS analysis revealed that IL17A promotes the recruitment of tumor- associated macrophages and other key myeloid subsets into the metastatic liver environment. Further research, using mice with conditional knockout of IL17RC receptor in myeloid cells (Il17rc f/f -LysMCre) or hepatocytes (Il17rc f/f -AlbCre) also showed significance of IL17 signaling activation in CRC metastasis through two distinct mechanisms. Employing different techniques, from FACS, immunohistochemistry, to RNAseq and scRNAseq data analysis, we observed that local hepatic activation of IL17RC signaling recruits neutrophils and reduces infiltration of cytotoxic CD8+T and NK cells to the metastatic niche supporting tumor growth, while myeloid IL17RC signaling reshapes TME, including macrophages and neutrophils, enhancing CRC metastasis. Our research indicates that IL17 signaling plays a multifaceted pathogenic role in CRC progression by operating in at least several cell types, providing new insights into the basic biology of CRC metastasis and potentially illuminating the design and improvement of CRC treatment strategies. Citation Format: Katarzyna Chojnacka, Katrina Mae Reyes, Hana Tomizawa, Sergei Grivennikov. Multifaceted pro-metastatic role of IL-17 signaling in modulating the tumor microenvironment of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B018.

Abstract A033: Integrating spatial transcriptomics and second harmonic generation imaging to identify targets of supermere-associated Discoidin Domain Receptor 1 involved in collagen alignment

Abstract Immune checkpoint blockade has been shown to be an effective treatment for colorectal cancers (CRCs) highly infiltrated by CD8+ T cells. However, there is a paucity of CD8+ T-cell infiltration in the majority of CRCs. We previously identified the collagen-activated receptor Discoidin Domain Receptor 1 (DDR1) as a member of a four-gene signature associated with T-cell exclusion in CRC. The cleaved ectodomain (cECD) of DDR1 induces collagen alignment, leading to T-cell exclusion in a breast cancer model. We found that almost all DDR1 cECD is found in supermeres, a novel secreted nanoparticle identified by our lab, and that DDR1 cECD is required for supermere signaling in recipient cells. We hypothesized that supermere-associated DDR1 cECD signals to CRC stromal cells, leading to collagen alignment. To test this hypothesis, we developed a method to determine which genes are associated with collagen alignment and DDR1 expression. To do this, 30 μm thick CRC sections are imaged using a Nikon AX multiphoton microscope by second harmonic generation imaging, which permits label-free imaging of collagen fibers. Spatial heatmaps of the collagen alignment are generated from the resulting images. Spatial transcriptomics is performed on a serial tumor section using the Visium v2 platform and the gene expression matrix is integrated with the collagen alignment heatmap data. As proof-of-principle, two CRC tumors have been analyzed using this method. Highly aligned regions were found to be associated with expression of genes involved in extracellular matrix organization, keloidal collagen and specific fibroblast subtypes. Genes which may be regulated by DDR1 cECD and be involved in collagen alignment will be confirmed at the protein level by multiplexed immunofluorescence on serial sections and in vitro experiments. This method will provide a rich dataset to elucidate the roles of supermeres and DDR1 cECD in T-cell exclusion and collagen fiber alignment and may support the discovery of new strategies to overcome immune exclusion in CRC. Citation Format: Maxwell S. Hamilton, Oleg Tutanov, Harsimran Kaur, Alan J. Simmons, Clark Massick, Kasey Vickers, Ken S. Lau, Ambra Pozzi, Robert J. Coffey. Integrating spatial transcriptomics and second harmonic generation imaging to identify targets of supermere-associated Discoidin Domain Receptor 1 involved in collagen alignment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A033.

Abstract C019: IL27R signaling regulates neutrophils maturation, activation and function in colorectal cancer-liver metastases

Abstract Colorectal cancer (CRC) is the third most common cancer and fourth cause of cancer death worldwide. The liver is the most common organ for CRC metastasis, which is a major cause of death for CRC patients. Therefore, a better understanding of mechanisms facilitating CRC liver metastasis is in urgent need. IL27 is a member of IL6/IL12 cytokines superfamily which have a critical role in tumor microenvironment to affect tumorigenesis and metastasis. IL27 is secreted by activated macrophages and dendritic cells, and IL27R is expressed in various immune cells, mediating IL27-dependent pro-inflammatory or anti-inflammatory immune responses. However, the role of myeloid IL27 signaling in CRC-liver metastasis remains unclear. To study the role of IL27R signaling in myeloid cells, we generated Il27ra fl/fl mice and crossed them with LysM cre deleter to obtain LysM cre+ Il27ra f/f mice. Using MC-38 CRC cells portal vein injection model, we found that myeloid IL27Ra deletion leads to increased CRC-liver metastasis accompanied by increase in neutrophils, particularly Ly6G+Cxcr2-CD101- immature neutrophils, in circulation as well as tumors in LysM cre+ Il27ra f/f mice. Single-cell sequencing of tumor-infiltrating immune cells revealed that lack of IL27Ra in myeloid cells promoted neutrophil recruitment and degranulation as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS) production but inhibited neutrophil maturation and production of pro-inflammatory chemokines and cytokines such as CXCL10, CSF1 and TNF. Furthermore, IL27Ra deficient neutrophils displayed heightened inflammatory response when stimulated with LPS in vitro. Collectively, our work reveals novel role of myeloid IL27Ra signaling that inhibits metastatic liver colonization by promoting neutrophil maturation, restricting neutrophil infiltration and degranulation. Citation Format: Jiani Zhu, Zhengzheng Shi, Ekaterina Koltsova. IL27R signaling regulates neutrophils maturation, activation and function in colorectal cancer-liver metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C019.

Concentration and composition of circulating vesicles of adipocytic origin in patients with colon polyps and colorectal cancer

Extracellular vesicles (EVs) are a heterogeneous population of membrane particles less than 1 μm in size, secreted by various cell types. Most EVs circulating in human blood are particles of platelet, leukocyte, erythrocyte and endothelial origin. The composition of circulating adipocyte EVs in various pathological conditions has been virtually unknown. Small EVs from the blood plasma of patients with colorectal cancer (CRC) and colon polyps with obesity or metabolic syndrome were isolated by ultrafiltration with double ultracentrifugation. To study the composition of adipocyte EVs, immunoprecipitation in combination with Western blotting and flow cytometry were used. Vesicle fractions (FABP4- and CD11b-immunoprecipitated EVs, as well as EVs contained in the supernatant after removal of CD11b-positive EVs) contained a complex of adipocyte markers (FABP4, PPAR-γ and perilipin 1). EVs of monocyte-macrophage origin precipitated on CD11b-coated particles in CRC patients without obesity were characterized by combined overexpression of FABP4 and perilipin 1, while such overexpression was not typical for CRC patients with metabolic syndrome or obesity. The fraction of truly adipocyte vesicles (supernatant after removal of CD11b-positive EVs) was characterized by the presence in all patients of a complex of adipocyte markers with predominant expression of FABP4 in both patients with metabolic syndrome/metabolically healthy obesity and patients without metabolic disorders. To correctly characterize circulating EVs of patients without obesity, it is first necessary to remove the fraction of CD11b-positive monocyte-macrophage EVs from EV preparations by immunoprecipitation or similar methods, and in the supernatant after removal/sorption of precipitated EVs, the composition of adipocyte vesicles can be studied using a set of markers (FABP4, PPAR-γ, perilipin 1, etc.). Moreover, in patients with metabolic disorders, taking into account the insignificant expression of FABP4 in CD11b-immunoprecipitated EVs, preliminary depletion of vesicle preparations is apparently not so necessary.

Abstract A008: Microenvironmentally released cytokines mediate organ specific transcriptional profiles for metastatic colorectal cancer

Abstract Metastatic disease represents a complex series of interaction between tumors and their surrounding microenvironment. Here we utilize model systems to define organ specific transcriptional signatures present in metastatic seeding. We have identified unique epigenetic programing necessary for the colonization of the liver or the lung by colorectal cancer. We have shown that manipulation of master regulators of these signatures in vitro and in vivo changes the metastatic potential of the tumor. In specific, we have found that native cytokines within the liver and lung are engaged by the metastatic tumor cells to promote this reprograming. In the case of the liver, we have identified hepatocyte released CCL2 acts on metastasizing tumors to promote colonization. Through in vitro and in vivo models, we showed that CCL2 engagement drives upregulation of the transcription factor TCF7 and subsequent enhancer reprograming to promote survival of the metastatic cells in the liver. In the lung, we have identified additional, unique secreted cytokines which lead to the upregulation of other TCF family members. Together this data identifies an important signaling nodes in colorectal cancer. Here we propose a model in which secreted factors by the host organ, such as CCL2, reprogram genes within the tumor cell to promote growth and survival of the metastatic cell in foreign microenvironments such as the lung or liver. Targeting these proteins may kill existing metastatic lesions as well as block new metastases from forming which will be essential in improving the outcomes of patients with oligometastatic and premetastatic disease. Citation Format: Charlie Niesen, Nathan Wu, Jonathan Rennhack. Microenvironmentally released cytokines mediate organ specific transcriptional profiles for metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A008.