Abstract 1093: The role of cellular adhesion in escaping prostate cancer tumor dormancy.
Authors: Ruppender Nazanin S. , Larson Sandy , Lakely Bryce , Brown Lisha , Coleman Ilsa , Coleman Roger , Nelson Peter , Corey Eva , Snyder Linda , Vessella Robert , Morrissey Colm 
Published: August 2014

Dissemination of prostate cancer (PCa) cells to the bone marrow appears to be an early event in the PCa disease process. In some patients, these disseminated tumor cells (DTC) proliferate to form active metastases after a prolonged period of undetectable disease following initial treatment. This time period that precedes recurrence is often referred to as tumor dormancy. Prevention of PCa recurrence would present a significant clinical advantage, as patients with bone metastases ultimately stop responding to second line therapies and eventually succumb to the disease. Understanding the biology of tumor dormancy and the mechanism(s) of release from dormancy will allow us to determine which patients may recur and identify possible targets for therapy to prevent disease recurrence.

The microenvironment significantly influences tumor cell proliferation and the formation of metastases. With respect to dormancy, cues from the microenvironment have been shown to regulate integrin β1 signaling in breast and epidermoid carcinoma to promote cell proliferation. However, mechanisms of PCa dormancy remain unknown. Additionally, PCa is a heterogeneous disease, further complicating the identification of mechanisms pertinent to dormancy. Here, we show that 5 different LuCaP PCa xenografts, which appear dormant in vitro, are induced to proliferate through contact with each other and activated bone marrow stroma. Furthermore, this effect can be reproduced by constitutively activating the phosphorylation of myosin light chain II, a downstream effector of integrin β1.

It has previously been shown that dormant breast cancer cells lacking integrin β1 signaling experience cell cycle arrest in the G1 phase. Thus, we examined changes in genes implicated in cell cycle progression in LuCaP PCa xenografts with constitutively active myosin light chain kinase (MLCK). We find that cyclin dependent kinase 6 (CDK6) is consistently upregulated in LuCaP xenografts with constitutively active MLCK. Furthermore, the transcription factor E2F4, which is implicated in growth arrest, is consistently downregulated. CDK6 is important in release from G1, and has previously been shown to associate with the androgen receptor, a critical player in PCa growth. Taken together, these data point to a potential mechanism by which PCa cells are released from dormancy to form lethal metastases. Targeting this mechanism could provide powerful new treatment opportunities that could reduce the lethality of PCa.

Citation Format: Nazanin S. Ruppender, Sandy Larson, Bryce Lakely, Lisha Brown, Ilsa Coleman, Roger Coleman, Peter Nelson, Eva Corey, Linda Snyder, Robert Vessella, Colm Morrissey. The role of cellular adhesion in escaping prostate cancer tumor dormancy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1093. doi:10.1158/1538-7445.AM2013-1093