Genetic Ablation of the Tetraspanin CD151 Reduces Spontaneous Metastatic Spread of Prostate Cancer in the TRAMP Model

Ben T Copeland,Matthew J Bowman,Leonie K Ashman

doi:10.1158/1541-7786.mcr-12-0468

Abstract

Tetraspanins are integral membrane proteins that associate with motility-related molecules such as integrins. Experimental studies have indicated that they may be important regulators of tumor invasion and metastasis, and high expression of the tetraspanin CD151 has been linked to poor prognosis in a number of cancers. Here, we show for the first time that genetic ablation of CD151 inhibits spontaneous metastasis in a transgenic mouse model of de novo tumorigenesis. To evaluate the effects of CD151 on de novo prostate cancer initiation and metastasis, a Cd151(-/-) (KO) murine model was crossed with the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Mice were analyzed for initiation of prostate tumor by palpation and primary tumors were analyzed by immunohistochemistry. Liver and lungs were examined for incidence and size of spontaneous metastatic lesions by histopathology. Knocking-out Cd151 had no significant effect on prostate cancer initiation or on expression of markers of proliferation, apoptosis, or angiogenesis in primary tumors. However, it did significantly decrease metastasis in a site-specific fashion, notably to the lungs but not the liver. Thus, CD151 acts principally as promoter of metastasis in this model. Prostate cancer is the second highest cause of cancer-related deaths in men in most Western countries, with the majority of deaths attributed to late-stage metastatic disease. CD151 may prove to be a valuable prognostic marker for treatment stratification and is a possible antimetastatic target.

Highlights

Prostate cancer is the most commonly diagnosed cancer in developed countries and the second most common cause of deaths in males
The Transgenic Adenocarcinoma of Mouse Prostate (TRAMP)-negative Cd151 wt and Cd151 KO F1 (C56BL6 xFVB/N) animals were analyzed for any developmental irregularities resulting from the Cd151 KO
It was essential to investigate if the ablation of Cd151 in the TRAMP-positive animals affected the expression levels of the oncogenic SV40 T-ag transgene

Summary

Introduction

Prostate cancer is the most commonly diagnosed cancer in developed countries and the second most common cause of deaths in males. Because of the advent of prostate-specific antigen (PSA) screening, approximately 90% of patients still have the cancer confined to the prostate gland at diagnosis [1]. The majority of deaths from prostate cancer are attributed to the incurable, late-stage, metastatic form of the disease [2]. The molecular mechanisms that drive the metastatic cascade in prostate cancer are poorly understood altered expression of various genes are known to influence metastasis [3]. Prostate cancer remains somewhat indolent in some patients while others develop aggressive metastatic forms of the disease. Understanding the molecules that influence the metastatic cascade may prove beneficial as prognostic markers and for patients

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Conclusion