Abstract
Neoadjuvant chemotherapy (NACT) is a treatment modality whereby chemotherapy is used as the initial treatment of HNSCC in patients presenting with advanced cancer that cannot be treated by other means. It leads to shrinkage of tumours to an operable size without significant compromise to essential oro-facial organs of the patients. The molecular mechanisms behind shrinkage due to NACT is not well elucidated. Eleven pairs of primary HNSCCs and adjacent normal epithelium, before and after chemotherapy were screened for cell proliferation and apoptosis. This was followed by immunohistochemical analysis of some cell cycle (LIMD1, RBSP3, CDC25A, CCND1, cMYC, RB, pRB), DNA repair (MLH1, p53) and apoptosis (BAX, BCL2) associated proteins in the same set of samples. Significant decrease in proliferation index and increase in apoptotic index was observed in post-therapy tumors compared to pre-therapy. Increase in the RB/ pRB ratio, along with higher expression of RBSP3 and LIMD1 and lower expression of cMYC were observed in post-therapy tumours, while CCND1 and CDC25A remained unchanged. While MLH1 remained unchanged, p53 showed higher expression in post-therapy tumors, indicating inhibition of cell proliferation and induction of apoptosis. Increase in the BAX/BCL2 ratio was observed in post-therapy tumours, indicating up-regulation of apoptosis in response to therapy. Thus, modulation of the G1/S cell cycle regulatory proteins and apoptosis associated proteins might play an important role in tumour shrinkage due to NACT.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a major form of cancer in the Indian subcontinent, accounting for about 30-40% of all cancer types (Tripathi et al, 2003)
Neoadjuvant chemotherapy (NACT) is a treatment modality whereby chemotherapy is used as the initial treatment of HNSCC in patients presenting with advanced cancer that cannot be treated by other means
This was followed by immunohistochemical analysis of some cell cycle (LIMD1, RBSP3, CDC25A, CCND1, cMYC, RB, pRB), DNA repair (MLH1, p53) and apoptosis (BAX, BCL2) associated proteins in the same set of samples
Summary
Head and neck squamous cell carcinoma (HNSCC) is a major form of cancer in the Indian subcontinent, accounting for about 30-40% of all cancer types (Tripathi et al, 2003). Induction chemotherapy, called neoadjuvant chemotherapy (NACT), followed by surgery is the choice of treatment for patients presenting with locally advanced, unresectable disease. Inactivation of MLH1, a DNA repair protein and p53 occurred at mild dysplastic stage, indicating the impairment of DNA repair as an early event in the development of the tumor (Maiti et al, 2012). To understand the molecular mechanism of tumor shrinkage in HNSCC due to NACT, we wanted to analyze the alterations of these genes in tumors before and after chemotherapy For this reason, firstly we have analyzed proliferation and apoptosis in 11 pairs of pre- and posttherapy HNSCC tumors from the same patients, along with their respective adjacent normal tissues. Our data suggests that inhibition of cellular proliferation and induction of apoptosis might be the reason for tumor shrinkage
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