Differential requirement for Src-family tyrosine kinases in the initiation, progression and metastasis of prostate cancer, "Beyond the Abstract," by Irwin H. Gelman, PhD

BERKELEY, CA (UroToday.com) - Two of the most important issues currently debated in the prostate cancer (CaP) treatment field include i) better identification of markers and pathways that predict which early CaP cases will progress to malignancy, and ii) how to provide durable treatment to patients whose recurrent metastatic disease arises after failure of androgen deprivation therapy. Multiple studies have shown that Src-family tyrosine kinases (SFK) are activated during CaP progression, most likely resulting from the activation of upstream receptor tyrosine kinases known to be overexpressed or mutationally activated in advanced CaP disease.

Building on data that SFK could function as drivers of CaP malignancy and post-castration recurrence, we asked whether 3 such family members known to be expressed in prostate epithelial cells, Src, Lyn and Fyn, played direct roles in i) early-stage CaP adenocarcinoma initiation, ii) later-stage transition to neuroendocrine (NE) disease, and iii) metastatic progression. Our technique was to cross transgenic mouse strains lacking Src, Lyn or Fyn with a transgenic mouse CaP model, TRAMP, in which CaP progression is induced by the prostate epithelial-specific expression of the SV40 T-antigen, which binds to and inactivates the Rb and p53 tumor suppressor proteins. Our data indicated that the loss of Src, Lyn or Fyn had no effect on NE transition, either in regards to progression of lesions in the prostate or in multiple metastatic sites. In contrast, the initiation of CaP adenocarcinomas and formation of late NE metastases were severely suppressed in mice lacking Src and partially suppressed by the lack of Lyn, however, the absence of Fyn had no effect on these parameters of oncogenesis.

These data suggest that in this model, CaP initiation is differentially dependent on specific SFK members, with Src being the most critical. We also detected a paradoxical role for SFK members in regards to late-stage metastasis. This is based on the fact that a small percentage (< 5%) of TRAMP mice fail to develop CaP lesions by 33 weeks of age (typically advancing to prostatic intraepithelial neoplasia), yet notably, these mice exhibit highly aggressive metastatic adenocarcinomas, especially in the lung. Mice lacking Lyn or Fyn suffered five- to seven-fold increases, respectively, in the incidence of such disease (the rarity of any CaP-related disease in the Src-null mice made it impossible to assess Src’s role in this phenomenon). Thus, our model validates the notion that therapeutically targeting SFK would suppress CaP progression in humans. However, our data that at least Fyn and Lyn may play suppressive roles in alternative pathways controlling metastatic progression suggests that treatment with broad SFK kinase inhibitors might select for therapy-induced metastasis.

Written by:
Irwin H. Gelman, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

John and Santa Palisano Chair of Cancer Genetics
Professor of Oncology
Director, Cell & Molecular Biology Academic Program
Leader, Comprehensive Cancer Center Genetics Program
Roswell Park Cancer Institute
Buffalo, NY USA

Differential requirement for Src-family tyrosine kinases in the initiation, progression and metastasis of prostate cancer - Abstract

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