Abstract
Prostate cancer (PC) is a leading cause of death in men however the factors that regulate its progression and eventual metastasis to bone remain unclear. Here we show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model TRAMP in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested it showed that twice weekly injections of anti-WISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigel™ barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer.
Highlights
Being the second leading cause of cancer death in men of all races, prostate cancer is a major health concern for men [1,2]
In this experiment core biopsies from low and high grade cancers (I was lowest, IV was highest) and were stained for immunohistochemistry using the WISP1 antisera and compared with staining using IgG as a negative control. Evaluation of this staining by at least two independent observers revealed that WISP1 is expressed to a greater extent in the prostate cancer compared to normal controls (Figure 1A) and that it was primarily located in the stroma tissue surrounding the tumor and to some extent in the epithelial tissue
Our analysis showed that when all the grades were grouped together WISP1 was significantly higher in serum from patients with prostate cancer (PCA) compared to normal controls (NL) (Figure 1C)
Summary
Being the second leading cause of cancer death in men of all races, prostate cancer is a major health concern for men [1,2]. Like many other dangerous cancers, prostate cancer cells have a very high incidence of migrating from the primary tumor to distant sites where they are a more direct cause of morbidity and mortality [4]. A frequent site for the metastasis of prostate cancer is to bone, when the cancer progresses to this stage, it is usually incurable [5,6,7]. There is a critical a need to 1) understand what factors contribute to the disease progression in the prostate, 2) understand how and why prostate cancers ‘‘home’’ to bone and, further, 3) devise new ways to prevent this complex and devastating process. New information about candidate proteins involved in this process could, potentially be used to develop new therapies to reduce the spread and establishment of the disease at distant sites such as bone
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