Since its discovery as an inhibitor of cyclin dependent kinase 4 and 6, the tumor suppressor p16 has continued to gain widespread importance in cancer. The high frequency of deletions of p16 in tumor cell lines first suggested an important role for p16 in carcinogenesis. This initial genetic evidence was subsequently strengthened by numerous studies documenting p16 inactivation in kindred with familial melanoma. Moreover, a high frequency of p16 gene alterations were found in primary tumors, while recent studies have identified p16 promoter methylation as a major mechanism of tumor suppressor gene silencing. Additional insight into p16's role in cancer has come from the genetic analysis of precancerous lesions and various tissue culture models. Micro-satellite analysis of human aerodigestive tumors suggests that p16 loss occurs early and often in the progression to malignancy and likely results in the clonal expansion of premalignant cells.

We believe that p16 has a biological role independent of it's ability to regulate G1/S cell cycle progression. It is well known that primary epithelial cells will undergo apoptotic cell death (Anoikis) when they lose contact with the extra-cellular matrix, unlike their malignant counterparts. Based on this hypothesis, we have observed that the reintroduction of p16 into squamous cell carcinoma cell lines deprived of contact with the extra-cellular matrix will induce apoptosis. The identification of p16 as a regulator of anoikis (induction of apoptosis after loss of anchorage), is an important first step in linking the observations from molecular genetic analysis (p16 loss occurs early and often) with data from biochemical studies (p16 as a regulator of the G1/S restriction point). Consequently, during malignant progression, early p16 loss allows epithelial cells to become resistant to anoikis. This results in an important growth advantage and allows for the clonal expansion of premalignant cells. This model has particular relevance to cancers of the aerodigestive tract (i.e., lung, esophagus, and head and neck squamous cell cancer), where premalignant fields of clonal cells have been identified and are potentially condemned to a fate of progression to cancer.

Identification and characterization of a novel p16-dependent checkpoint that is independent of p16's ability to elicit cell cycle arrest
Principal Investigator: James W. Rocco MD, PhD
Group Members: Takafumi Katayama, MD; Jennifer Shin, MD