Colorectal Cancer

Colorectal cancer is the third most common cancer in humans and is the second leading cause of cancer in the United States. Currently, two multistage progression models exist that describe the molecular characteristics of the development of colorectal cancer (CRC) from normal epithelial colon cells over crypt foci, to the development of polyps and subsequent progression to adenomas and advanced CRC. In the classical model, loss of the APC gene, which results in constitutive activation of ß-catenin and the acquisition of progenitor-like phenotype, is likely the initial driver mutation. Additional mutations in MAPK (KRAS, Erbb2), TGFß (TGFBR2, SMAD4), PI3K (PI3KCA) signaling and p53 accumulate over the course of disease progression. The serrate pathway is characterized by microsatellite instability (although microsatellite stable tumors occur) and frequent CpG island promoter hypermethylation, resulting in epigenetic silencing of several tumor suppressor genes (including MSH1, which promotes microsatellite instability). This subset of CRC is further characterized by mutations in BRAF, rather than KRAS, and APC loss does not seem to be an initiating event. Advances in the molecular understanding led to the approval of several targeted therapies including antiangiogenic therapy and EGFR inhibitors, which can be added to the standard of care chemotherapeutic agents in patients with metastatic CRC. Additional drugs currently undergo clinical testing to treat a subset of metastatic CRCs, like BRAF inhibitors, which are already approved for the treatment of other cancers.

A growing field of interest in CRC research is the role of the fecal microbiome in disease initiation and progression. Although CRC pathogenesis has long been associated with diet and lifestyle, which affect the composition of the gut microbiome, the molecular mechanisms by which the gut microbiome affects CRC carcinogenesis and progression are emerging. The tumor-promoting activity is partially attributable to specific pathogens that affect pro-inflammatory interactions with the host cells, and it is becoming increasingly clear that the microbial community as a whole, and particularly their metabolic activity, influences intestinal homeostasis. The microbiome may elicit tumor suppressor activity by influencing host immunity and apoptosis signaling via short chain fatty acids, their major fermentation products. On the other hand, several bacterial metabolites can cause direct DNA damage or induce a pro-inflammatory environment, which promotes tumorigenesis. Additionally, the microbiome – immune system interaction also determines optimal responses to therapeutic interventions. Understanding the complex molecular interactions between the microbiome and the host may have important implications in diagnosis, treatment stratification, and therapy of CRC.

TICC Faculty who are involved in colorectal cancer research:

Dov Hershkovitz

Gad Rennert

Gil Bar Sela

Hossam Haick

Ofer Ben Izhak

Ron Epelbaum

Yehuda Chowers

Yehuda G. Assaraf

Yuval Shaked