Colorectal Cancer

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 Ancillary Material Gradeenvironment, 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.

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 RNAscope^TM, is necessary to determine whether or not a tumor will respond to certain drug therapies. For example, a tumor bearing KRAS^G12C 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 KRAS^G12C 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.

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