Colorectal Cancer

Colorectal cancer (CRC) is the 2nd most lethal and 3rd most prevalent cancer worldwide. Screening has largely reduced the incidence of new CRC cases in several regions such as the USA and Europe, however 50% of both new cases and deaths are from the Asia Pacific region.

CRC progression follows a well-defined sequence from adenoma (benign epithelial tumor) to carcinoma (abnormal cells that divide uncontrollably and may metastasize). Due to this predictable pathway, the removal of adenomatous polyps at colon screenings, along with early detection and diagnosis, are the best methods for preventing disease progression. Polyps can be analyzed with immunohistochemistry to determine whether further treatment is needed.

Complete surgical removal of a tumor remains the best way to treat CRC; later stage cancer may require additional treatments, of which there are a range of clinical options. Genetic analysis of CRC tumor tissue may also be used to determine the most effective treatment; this is crucial as some medications can only be used to treat tumors with specific mutations.

Research Areas
Literature (14)
Pathways (4)

Colorectal Cancer Metabolism

CRC is a complex disease influenced by epigenetics, mutagenic and environmental factors. The tissues of the colon are exposed to a wide variety of compounds from the environment, diet, gut microflora (largely bacteria) and the resulting metabolic products of the gut microbiome. Interactions with bacteria are essential for the health of the digestive system; for example, the breakdown of dietary fiber by gut bacteria provides Butyrate (Cat. No. 3850), the main source of energy for healthy cells of the colorectal epithelium.

Butyrate itself induces death in CRC cells, inhibits glucose transport, and can be used to increase the sensitivity of CRC cells to other treatments, such as 5-Fluorouracil (Cat. No. 3257). CRC cells favor glucose over butyrate as an energy source, so glucose transporter (GLUT) inhibitors may be useful for studying CRC metabolism.

Colorectal Cancer and Inflammation

Prolonged inflammation, such as from inflammatory bowel disease, results in cell damage and is related to increased risk of developing cancer; inactivation of p53 occurs in around 85% of colitis-associated cancers. The tumor microenvironment (TME) of colorectal tumors is varied and unique to each patient, as is the microbiome within the colon. The mix of gut microflora is altered during inflammation and may directly influence the risk of developing CRC. An additional risk factor is the use of immune suppression, e.g. glucocorticoids, to treat inflammation. Although they may be critical in treating the inflammatory processes, these medicines can also promote carcinogenesis.

Molecular Subtypes of Colorectal Cancer

There are several ways in which CRC can be classified. One classification approach is the Consensus Molecular Subtype. The four Consensus Molecular Subtypes (CMS) are characterized by the presence or absence of certain features, summarized in Table 1. These pathways rarely overlap, which helps when targeting therapies.

Microsatellite instability (MSI) is caused by defects in the DNA mismatch repair system. MSI tumors tend to have a higher mutation burden and produce neoantigens that trigger an immune response - they can be studied with immune checkpoint inhibitors such as (D)-PPA 1 (Cat. No. 6515). The chromosomal instability (CIN) pathway results in a widespread loss of tumor suppressor gene functions (KRAS, TP53, SMAD4, APC), chromosomal copy number abberrations and structural alterations or defects. The CpG island methylator phenotype (CIMP) pathway leads to hypermethylation of promoter sequences of tumor suppressor genes. These specific features of each subtype can be used to refine both further research and treatment options.

Table 1. Consensus Molecular Subtype classifications of colorectal cancer. (CIMP = CpG island methylator phenotype, SCNA = somatic copy number alteration)
Type Name Features Mutation/Changes CIMP SCNA Products for Research
CMS1 (14%) Microsatellite Instability Immune (MSI) Immune activation, microsatellite instability, hypermutation BRAF V600E and TGFBR2 mutations, JAK-STAT and caspases + Low SJF 0628, Vemurafenib, CG 858
CMS2 (37%) Canonical Epithelial; WNT and MYC signaling activation; chromosomal instability APC and TP53 mutations; WNT and b-catenin/MYC activation - High KJ Pyr9, WIKI4
CMS3 (13%) Metabolic Metabolic dysregulation; epithelial KRAS and APC mutations Low Intermediate LC 2, MRTX 849
CMS4 (23%) Mesenchymal Angiogenesis; matrix remodeling; stromal invasion TGF-β activation - High A 83-01

Genetics and Genotyping of Colorectal Cancer

The predictable pathway of CRC cancer from adenomatous polyp to carcinoma is characterized by several genetic changes including activation of Wnt/β-catenin, followed by RAS/RAF mutations then loss of p53 function.

Of over 140 known cancer driver genes, the most common in CRC are APC, KRAS, BRAF, TP53 and PIK3CA. APC, the most commonly inactivated gene in colon cancer, is a tumor suppressor that is inactivated in CRC. It regulates β-catenin and interacts with cell adhesion molecules so may also affect metastasis. KRAS is commonly mutated in CRC (up to 40% of cases) and is involved in regulating cell proliferation. BRAF is a serine/threonine protein kinase involved in cell division; mutations in this gene can lead to unchecked cell division and therefore tumor growth. TP53/p53 regulates genes that control tumor suppressor functions; inactivation of TP53 facilitates tumor progression and may also be involved in the development of CRC in patients with inflammatory bowel diseases.

Genotyping of tumor tissue, for example by using RNAscopeTM, is necessary to determine whether or not a tumor will respond to certain drug therapies. For example, a tumor bearing KRASG12C mutations will respond to MRTX 849 (Cat. No. 7488) treatment, but not to drugs that only inhibit the wild-type KRAS. A Degrader such as LC 2 (Cat. No. 7420) can be used to degrade KRASG12C but will not degrade other mutations or wild-type KRAS, allowing for specific targeting of cancer-related proteins.

Intestinal Stem Cells

The intestinal epithelium is the most rapidly self-renewing tissue in mammals, a feature that makes colorectal cells prone to the accumulation of somatic mutations. The rapid turnover is a result of cycling crypt base columnar Lgr5+ intestinal stem cells that renew the colonic epithelium every 3-5 days.

Leucine-rich-repeat-containing G-protein-coupled receptor 5 (Lgr5) is a Wnt target gene; most CRCs show hyperactivation of the WNT pathway. Lgr5 expression also influences other pathways and processes, such as notch signaling, cell migration and metastasis. Paneth cells, found adjacent to and around intestinal stem cells (ISCs), excrete factors such as Wnt ligands into the microenvironment that maintain the ISC state Wnt inhibitors may therefore be useful to learn more about the effects of this pathway in CRC.

Patient Derived Xenografts and Organoids

Organoids and patient derived xenografts (PDX) can be grown from cells or tissue taken directly from a patient. A single Lgr5+ cell can generate a gut organoid complete with crypt and villus structures, providing a way to test potential drug therapies in cells carrying the relevant genetic mutations.

PDXs are sections of tumor removed from a patient during biopsy that are implanted into and grown in immunocompromised mice. They allow the tumor to be treated in real-time, maintaining the structural and TME factors, and provide pharmacokinetic information to more accurately reflect tumor responses to drug therapies.

New and Top Products for Colorectal Cancer Research

Target Top Products New Products
ALK A 83-01 (Ancillary Material Grade available),
SB 431542 (GMP available),
Ceritinib, TL 13-112
 
ATM KU 55933, VE 821, AZ 5704  
AXL XL 184  
BRAF SB 590885, SJF 0628, CG 858  
EGFR Gefinitib-based PROTAC® 3,
Iressa (Ancillary Material Grade available),
Erlotinib, EMI 48
 
ERBB2 Neratinib, SJF 1528 Tucatinib (coming soon)
HGF/MET SU 5416, Crizotinib, SJF 8240  
HIPPO Verteporfin, XMU MP 1, (R)-PFI 2  
IGFR Ceritinib, 6bK Linsitinib
JAK PKF 115584 (Calphostin C), FH 535  
KRAS LC 2 MRTX 849
MAPK SB 202190, PD 0325901, SB 706504, SJFα  
mTOR Rapamycin, Torin 1  
MYC KJ Pyr 9, 10058-F4  
NOTCH DAPT (Ancillary Material Grade available),
Compound E, TCH-165,
DBZ (Ancillary Material Grade available)
 
RET SU 5416, SPP 86 Vandetanib, Selpercatinib
SMARCA4 SGC SMARCA-BRDVIII FHT 2344 and FHT 1015 (coming soon)
SRC Bosutinib, A 419259  
VEGF/R SU 5402, SU 5416 Cediranib, Vandetanib
WNT CHIR 99021 (GMP available),
IWP 2, Wnt-C59, LP 922056, FH 535
WIKI4 (Ancillary Material Grade available)
 
YAP Verteporfin  

PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.

Literature for Colorectal Cancer

Tocris offers the following scientific literature for Colorectal Cancer to showcase our products. We invite you to request* or download your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.


Cancer Research Product Guide

Cancer Research Product Guide

A collection of over 750 products for cancer research, the guide includes research tools for the study of:

  • Cancer Metabolism
  • Epigenetics in Cancer
  • Receptor Signaling
  • Cell Cycle and DNA Damage Repair
  • Angiogenesis
  • Invasion and Metastasis
Cell Cycle and DNA Damage Research Product Guide

Cell Cycle and DNA Damage Research Product Guide

This product guide provides a review of the cell cycle and DNA damage research area and lists over 170 products, including research tools for:

  • Cell Cycle and Mitosis
  • DNA Damage Repair
  • Targeted Protein Degradation
  • Ubiquitin Proteasome Pathway
  • Chemotherapy Targets
Pain Research Product Guide

Pain Research Product Guide

A collection of over 280 products for pain research, the guide includes research tools for the study of:

  • Nociception
  • Ion Channels
  • G-Protein-Coupled Receptors
  • Intracellular Signaling
Stem Cell Research Product Guide

Stem Cell Research Product Guide

This product guide provides a background to the use of small molecules in stem cell research and lists over 200 products for use in:

  • Self-renewal and Maintenance
  • Differentiation
  • Reprogramming
  • Organoid Generation
  • GMP and Ancillary Material Grade Products
Targeted Protein Degradation Research Product Guide

Targeted Protein Degradation Research Product Guide

This brochure highlights the tools and services available from Bio-Techne to support Targeted Protein Degradation research, including:

  • Active Degraders
  • TAG Degradation Platform
  • Degrader Building Blocks
  • Custom Degrader Services
  • Ubiquitin-Proteasome System Proteins and Assays
  • Assays for Protein Degradation
Epigenetics Scientific Review

Epigenetics Scientific Review

Written by Susanne Müller-Knapp and Peter J. Brown, this review gives an overview of the development of chemical probes for epigenetic targets, as well as the impact of these tool compounds being made available to the scientific community. In addition, their biological effects are also discussed. Epigenetic compounds available from Tocris are listed.

RAS Oncoproteins Scientific Review

RAS Oncoproteins Scientific Review

Written by Kirsten L. Bryant, Adrienne D. Cox and Channing J. Der, this review provides a comprehensive overview of RAS protein function and RAS mutations in cancer. Key signaling pathways are highlighted and therapeutic vulnerabilities are explored. This review also includes a detailed section on RAS drug discovery and targeting synthetic lethal interactors of mutant RAS. Compounds available from Tocris are listed.

Stem Cells Scientific Review

Stem Cells Scientific Review

Written by Kirsty E. Clarke, Victoria B. Christie, Andy Whiting and Stefan A. Przyborski, this review provides an overview of the use of small molecules in the control of stem cell growth and differentiation. Key signaling pathways are highlighted, and the regulation of ES cell self-renewal and somatic cell reprogramming is discussed. Compounds available from Tocris are listed.

Epigenetics Research Bulletin

Epigenetics Research Bulletin

Produced by Tocris and updated in 2014, the epigenetics research bulletin gives an introduction into mechanisms of epigenetic regulation, and highlights key Tocris products for epigenetics targets including:

  • Bromodomains
  • DNA Methyltransferases
  • Histone Deacetylases
  • Histone Demethylases
  • Histone Methyltransferases
Angiogenesis in Cancer Poster

Angiogenesis in Cancer Poster

Adapted from the 2015 Cancer Product Guide, Edition 3, this poster summarizes the pathogenesis of angiogenesis in cancer, as well as some of the main angiogenesis therapeutic targets.

Cancer Metabolism Poster

Cancer Metabolism Poster

Adapted from the 2015 Cancer Product Guide, Edition 3, this poster summarizes the main targets for cancer metabolism researchers. Genetic changes and epigenetic modifications in cancer cells alter the regulation of cellular metabolic pathways. These distinct metabolic circuits could provide viable cancer therapeutic targets.

Cell Cycle & DNA Damage Repair Poster

Cell Cycle & DNA Damage Repair Poster

In normal cells, each stage of the cell cycle is tightly regulated, however in cancer cells many genes and proteins that are involved in the regulation of the cell cycle are mutated or over expressed. Adapted from the 2015 Cancer Product Guide, Edition 3, this poster summarizes the stages of the cell cycle and DNA repair. It also highlights strategies for enhancing replicative stress in cancer cells to force mitotic catastrophe and cell death.

Gut Hormones Poster

Gut Hormones Poster

The gastrointestinal tract is the largest endocrine gland in the human body, secreting hormones that affect digestion, appetite and energy expenditure. Neuropeptide modulators and gut hormones that influence appetite are reviewed in this poster.

Stem Cells Poster

Stem Cells Poster

Written by Rebecca Quelch and Stefan Przyborski from Durham University (UK), this poster describes the isolation of pluripotent stem cells, their maintenance in culture, differentiation, and the generation and potential uses of organoids.

Pathways for Colorectal Cancer

JAK-STAT Signaling Pathway

JAK-STAT Signaling Pathway

The JAK-STAT signaling pathway has several roles, including the control of cell proliferation and hematopoiesis. It is the main signal transduction cascade from cytokine receptors.
TGF-β Signaling Pathway

TGF-β Signaling Pathway

The TGF-β signaling pathway is involved in the regulation of growth and proliferation of cells along with migration, differentiation and apoptosis.
Wnt Signaling Pathway

Wnt Signaling Pathway

The Wnt pathway is involved in cellular differentiation and proliferation in adult tissues and also during embryogenesis. Disturbances within the pathway may lead to the formation of tumors and promote metastasis.
p53 Signaling Pathway

p53 Signaling Pathway

p53 signaling plays an important role in the co-ordination of the cellular response different types of stress such as DNA damage and hypoxia. The downstream signals lead to apoptosis, senescence and cell cycle arrest.