Genetic and mechanistic determinants of prostate cancer progression and metastasis

Abstract

In order to study a complex biological phenomenon such as tumor cell metastasis, one must focus on examining discrete aspects of the process which are amenable to experimentation. In this thesis, I made use of xenograft and spontaneous in vivo mouse models of prostate cancer to approach this problem from two perspectives. First, I sought to identify genes which were involved with metastasis. Second, I focused on the mechanistic elements involved with tumor cell intravasation into lymphatics. The results from this work have shown that loss of Protein 4.1B, a 4.1/ezrin/radixin/moesin (FERM) domain-containing cytoskeletal protein, is a frequent event in prostate cancer. The significance of this finding was confirmed by experimental ablation of 4.1B, which enhanced tumor progression and metastasis, at least in part, by protecting cells against apoptosis. This thesis has also shown that metastatic dissemination to lymph nodes is mediated primarily by peritumoral lymphatic vessels, which surround the tumor at the invasive margins. In contrast, inhibition of intratumoral lymphatics did not affect metastatic spread, indicating that these vessels were unnecessary for tumor cell dissemination.

(cont.) The genetic and mechanistic findings from this thesis were consistent across both model systems examined, and are also in concordance with observations made in human clinical prostate cancer. Thus, the results of this work have contributed small pieces of knowledge to our overall understanding of how tumors initiate, and frequently complete, the elaborate and often lethal process of spreading throughout the body.