Shrey Thaker ‘22

The centerpiece of clinical struggle against cancer is the recurrence of the tumor following extensive chemotherapy. The most common chemotherapeutic agent dispatched to patients suffering from colon cancer is known as 5-Fluorouracil (5-FU) and its main mechanism of action includes inducing apoptosis by inflicting DNA damage and triggering the cell’s natural apoptotic pathways. While the initial effect of tumor cell death is intended and beneficial for the patient, the resulting cellular debris (parts of the dead cancer cell still remaining in the colon environment) may trigger additional oncogenic processes including angiogenesis (the generation of blood vessels around a tumor), inflammation, and heightened proliferation of existing tumor cells. The researchers at Harvard Medical School set out to investigate a potential molecular mechanism responsible for this paradoxical effect from 5-FU treatment. 

The team carried out a set of in vivo experiments using a mouse model and cellular debris generated from macrophages in vitro cells treated by 5-FU. After the debris was collected from the cells, it was then injected into the mouse along with a dose of 5-FU. After the treatment, the researchers quantified various proteins to assess which pathways were most affected and could have a mediator role in debris-induced oncogenesis. 

The most notable finding of the team included the prevalence of a protein called osteopontin in mice that were treated with the 5-FU and debris. Going further, the scientists discovered that inhibiting osteopontin with an antibody completely inhibited the cell debris-induced tumor growth. By recognizing a mechanism by which a current, widespread chemotherapy may induce recurrent tumors in patients, this group has paved the way for future combination therapies and improvements in the administration of such cytotoxic chemotherapy. The association of osteopontin and recurrence through the mechanism of cell debris generated by the initial action of 5-FU is a potential for approaching chemotherapy from a more holistic and safe background rather than risking a patient relapsing to such a horrible disease.

References 

1. J. Chang, et al. Chemotherapy-generated cell debris stimulated colon carcinoma tumor growth via osteopontin. Journal of the Federation of American Societies for Experimental Biology 33, 114-125 (2019). doi: 10.1096/fj.201800019RR
2.  Image retrieved from: https://commons.wikimedia.org/wiki/File:Papillary_Carcinoma_of_the_Thyroid.jpg