The following is a summary of “Complement is increased in treatment resistant rectal cancer and modulates radioresistance.,” published in the September 2024 issue of Oncology by O’Brien et al.

Resistance to neoadjuvant chemoradiation therapy (neo-CRT) presents a substantial clinical challenge in the management of locally advanced rectal cancer, often leading to suboptimal patient outcomes. The identification of new therapeutic targets and predictive biomarkers is imperative to enhance treatment efficacy. Emerging evidence points to the involvement of the complement system in mediating resistance to anti-cancer therapies. This study highlights the critical role of complement effectors, specifically C3 and C5, in contributing to radioresistance in rectal cancer cells. Notably, increased expression of C3 and C5, along with elevated levels of the anaphylatoxins C3a and C5a, was observed in radioresistant cancer cells. Functional studies demonstrated that modulating C3 expression significantly impacted cellular responses to radiation. 

Overexpression of C3 conferred enhanced radioresistance, while inhibition of C3 increased radiosensitivity, particularly at clinically relevant radiation doses. Further analysis revealed that C3 inhibition elevated levels of DNA damage and induced alterations in cell cycle distribution, leading to a radiosensitive phenotype. These findings suggest a pivotal role for C3 in reprogramming the tumor’s radioresponse. Additionally, the expression of complement effectors C3 and C5 and CFB, a key component of the alternative pathway, was significantly elevated in human rectal tumor tissues. Importantly, elevated pre-treatment serum levels of C3a and C5b-9 in patients with rectal cancer were correlated with poor therapeutic responses to neo-CRT and reduced survival rates. 

Collectively, this study provides compelling evidence for the involvement of the complement system in driving radioresistance in rectal cancer and identifies C3, C5, and associated complement components as potential biomarkers for predicting therapeutic response and clinical outcomes in patients undergoing neo-CRT. These findings offer new avenues for targeted therapeutic strategies aimed at overcoming radioresistance and improving survival in rectal cancer.

Source: sciencedirect.com/science/article/abs/pii/S0304383524006487