M.Sc Thesis


M.Sc StudentSadot Meshi
SubjectThe Effects of Cannabis on Colorectal
Cancer Harboring a Hereditary APC Mutation
DepartmentDepartment of Biology
Supervisor DR. David Meiri
Full Thesis textFull thesis text - English Version


Abstract

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. The leading initiator of CRC developments is adenomatous polyposis coli (APC) mutations which lead to its inactivation. This gene encodes a tumor suppressor protein that plays a key role in the canonical Wnt/β-catenin pathway.

When the Wnt signal is inactive, APC and additional proteins create a complex responsible for β-catenin phosphorylation, leading to its ubiquitylation and subsequent degradation by the proteasome. When Wnt signaling is activated by its ligands, β-catenin accumulates and binds to transcription factors, which leads to cell proliferation.

Most CRC cases are sporadic, however 1% is the result of familial adenomatous polyposis (FAP) syndrome.

FAP patients harbor a hereditary APC mutation which renders it inactive and unable to generate the β-catenin destruction complex. Thus, cellular β-catenin levels remain constantly high, leading to constitutive proliferation, which causes affected individuals to develop hundreds to thousands of polyps throughout the colon and rectum at young ages.


In the last decade, there has been intense interest in Cannabis as novel therapeutic agent for various conditions. Observational cases from hospitals indicate that Cannabis may reduce the amount of polyps in FAP patients. Therefore, we hypothesized that Cannabis may have anti-tumor effects on colon carcinoma cells with APC mutations.

We screened different Cannabis strains on LS1034, a human colorectal carcinoma cell line. In addition, we have established APCMin transgenic mice colony and generated APCMin driven mice organoids.

Our results show the effects of 3 different Cannabis extracts on apoptosis induction and Wnt/β-catenin pathway signaling on LS1034 cell line and APCMin Organoids. We found that treatment with specific Cannabis extracts reduces colorectal cancer cell viability and induces apoptosis. In addition, Cannabis extracts inhibited Wnt signaling by reducing β-catenin, HES1 and C-Myc levels.

Overall, our findings suggest that Cannabis treatment has the potential to serve as a preventive therapy for colorectal polyp development in APC deficient patients.