Pathology and Tumorigenesis
Colorectal cancers begin with epithelial cells that line the surface of the colon along finger-like projections called villi. The spaces between the villi are called crypts, and at the base of each crypt are immature stem cells that give rise to ever-renewing cells that migrate up the crypt and toward the tips of the villi. This normal cellular process is strictly governed by a balance of cellular renewal (normal proliferation) and cellular death (apoptosis), as well as elegantly choreographed expression of various genes along the path from immature stem cells to mature epithelial cells.
Early in the course of colon cancer development, however, the normal renewal of cells is disturbed. Cellular maturation (differentiation) is blocked and apoptosis is impaired leading to an accumulation of immature cells in the crypts. This is called an "aberrant crypt" and it is the first step in the carcinogenic process of colorectal cancers.29,30 These aberrant crypts almost always involve a genetic pathway that both embryos and colon cancer have in common, a pathway called Wnt.31 Many natural agents exert protective action through influencing this Wnt pathway, including components of black tea,32 green tea33 and turmeric.34
Once the aberrant crypt forms, it may go on to become a polyp, which is a growth along the lining of the colon that can be seen during a colonoscopy exam. Polyps are benign, but they can progress to adenomas, which are considered precancerous. If further mutations occur, an adenoma can then progress to cancer over years or decades. This is the primary reason that screening colonoscopies are recommended, to remove the polyps or adenomas before they have a chance to become cancer.
Genetic Abnormalities in Colorectal Cancer
Several genes and/or genetic processes are frequently malfunctional in colon cancer cells, and therefore have become intriguing targets for treatment interventions. Some dietary compounds have been shown to influence these genes and may modulate colon cancer development and progression.
KRAS is a gene that orchestrates cellular receptor sensitivity to a number of growth factors. When KRAS is activated, cellular proliferation is enhanced, while deactivated KRAS slows proliferation. In several types of cancer, including colorectal cancer, KRAS is mutated in such a way that causes it to be chronically activated, leading to unabated cellular proliferation. Mutations in KRAS are present in up to 40% of colorectal cancers.2
While drugs that directly target KRAS are not yet available, the mutational status of this gene helps determine the likelihood that certain anticancer agents will be effective. For example, the anti-EGFR antibodies cetuximab and panitumumab may be ineffective if activating mutations in KRAS are present.35
Several natural compounds have been shown to target the KRAS pathway, including:
- Perillyl alcohol, a substance extracted from citrus fruits36,37
- Fish oil39
- Tea polyphenols40
Epidermal growth factor receptor (EGFR) is a protein expressed on the surface of epithelial cells that variably regulates a number of pathways involved in cellular growth and proliferation. The KRAS pathway is among those that EGFR effects.
Overexpression of EGFR is observed in approximately 65–70% of colon cancers, and is associated with an advanced disease stage.2
Activation of EGFR stimulates KRAS-induced signal transduction leading to proliferation. However, in KRAS mutant (upregulation; overexpression) cancer cells, binding of EGFR is not necessary to activate KRAS. Therefore, medications sometimes used to treat colon cancer, called anti-EGFR antibodies, are only effective in patients not harboring a KRAS mutation.41 For example, cetuximab is a monoclonal antibody against EGFR indicated for metastatic colorectal cancer in patients not carrying a KRAS mutation.
Natural compounds shown to modulate EGFR include:
- Genistein (an isoflavone from soy)42
- American ginseng44
Note: Targeting EGFR directly may not be beneficial in a colorectal cancer patient overexpressing KRAS (constitutional activation). However, the aforementioned nutrients may also influence transcription downstream of EGFR and KRAS; thus, they may be capable of inducing cell cycle arrest in KRAS mutant or wild type cancer cells. For example, curcumin was shown to act synergistically with dasatinib to reduce KRAS mutant colon cancer cell viability through alternative pathways38; the other nutrients likely target additional pathways as well.
Microsatellite Instability (MSI) and Mismatch Repair Mutations
The human genome contains thousands of short, repeated base pair sequences called microsatellites, which vary in length from person to person, but are all the same length in an individual. DNA damage induced by factors such as oxidative stress and chemical carcinogens can cause dysfunction of genes responsible for ensuring that the microsatellites remain of consistent length; these genes are called mismatch repair genes. Mismatch repair gene mutations lead to microsatellite instability (MSI)—the lengthening or shortening of microsatellites. This causes dysfunction in the region of the genome containing the unstable microsatellites. If this occurs in a tumor suppressor region, the consequence can be uncontrolled cell growth, the hallmark of cancer.
Microsatellite instability is found in about 15% of colorectal cancers.45
Ironically, MSI (versus stable microsatellites) is associated with a better prognosis in colorectal cancer,41 likely for the same reasons that it leads to cancer in the first place—the cells are unable to repair major DNA damage and thus more readily succumb to apoptosis.
- Tea polyphenols have been shown to inhibit the proliferation of MSI colon cancer cells46,47;
- Cells with disrupted MMR function are highly sensitive to the apoptotic effects of curcumin.48