Colorectal cancer (CRC) has remained one of the most commonly occurring cancer and the related global burden is expected to increase. RT is used in the primary management of patients with anal (AC) or rectal cancer (RC), but unfortunately, individual anal/rectal tumors display wide ranges of radiosensitivity, and a significant part of patients do not benefit from RT. At now, there is no simple way of predicting tumor response or patient outcome with acceptable accuracy. Thus, considering that radiotherapy (RT) is associated with significant acute and late side-effects, that the costs related to treatment are significant and that anal/rectal patients could be managed with a wait-and-see approach, it could be strategic to identify biomarkers able to predict RT's outcome and the real need to then perform a surgical treatment.
Resistance to chemotherapy (CHT) and/or RT in cancer is linked to a subset of cancer cells termed ¿cancer stem cells¿ (CSCs), characterized from specific features including the expression of SPECIFIC miRNAs, non-protein-coding RNA molecules that regulate gene expression at the post-transcriptional level of nearly two thirds of all human genes, affecting thousands of physiological processes According with intra-tumor heterogeneity and the role of CSCs in cancer onset and radioresistance, profiling miRNAs from CSCs could represent a strategic tool to identify new prognostic-related biomarkers. By isolating CSCs from patients affected by AC or RC and profiling the miRNAs expression, the general aim of this collaborative project between radiotherapists, radiologists, surgeons and cell biologists is to develop a miRNAs-based test able to predict radio-chemo sensitivity of RC allowing the selection of patients who need for conventional or dose escalated neoadjuvant CHT-RT. The availability of such a predictive test for RC treatment would have several welcome consequences.
Curing anal and rectal cancer conventionally includes RT combined or not with cytotoxics drugs; however, a subgroup of patients undergoes a rapid disease progression or eventually relapses shortly after treatment ends because of the appearance of resistant cancer cells. Furthermore, conventional chemo/radiotherapy is associated with significant acute and chronic toxicity and with an increased risk of life threatening late events such as secondary malignancies. Consequently, the identification of new biomarkers able to predict the response to treatments of patients is urgently required. A newly emerged plausible explanation for tumor radioresistance is the existence of a subpopulation of cancer stem cells (CSCs) that are intrinsically more resistant to multiple clinical therapies and characterizing the roles of CSCs in both intrinsic and acquired radioresistance and identifying the molecular pathways that maintain CSC stemness are of paramount importance in improving the efficacy of cancer treatments. In this regards, microRNAs (miRNAs), non-protein-coding RNA molecules that regulate gene expression at the post-transcriptional level of nearly two thirds of all human genes, have been shown to play a key role in sustaining CSCs homeostasis and aggressiveness and profiling miRNAs from CSCs could represent a strategic tool to identify new prognostic-related biomarkers. Based on this evidence, we believe that the evaluation of miRNAs profiling in CSCs from AC and RC might provide novel CSCs-related biomarkers for an early diagnosis and a more appropriate stratification into risk classes and a deeper insight into the molecular mechanisms underlying radioresistance of this tumors. Furthermore, the identification of the molecular targets and signal pathways modulated by these radioresistance-related miRNAs might help in finding new radiosensitizing therapeutic strategies for the management of AC and RC patients.