The Effects of Growth Factors Associated with Osteoblasts on Prostate Carcinoma Proliferation and Chemotaxis: Implications for the Development of Metastatic Disease*

Abstract

The extensive mortality and morbidity associated with prostate cancer is caused by the high prevalence of metastatic disease at the time of diagnosis. The area most frequently involved in metastatic prostate cancer is the skeleton. Unlike other cancers, which metastasize to bone and destroy the bone matrix, prostate cancer is unique in that it is osteogenic, resulting in the formation of dense, sclerotic bone with high levels of osteoblastic activity. We proposed that factors produced by bone cells may be responsible for the development of prostate carcinoma metastasis. We studied the effects of these growth factors on prostate cell proliferation by [3H]thymidine incorporation and chemotaxis by the double-filter chamber method. Three prostate carcinoma cell lines were studied, LNCaP (androgen responsive) and PC-3 and DU-145 (androgen unresponsive). The bone-associated growth factors tested were: insulin-like growth factors I and II (IGF-I, IGF-II), transforming growth factor beta, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha), IGF-I and IGF-II significantly increased proliferation in all three cell lines, whereas IL-6, TNF-alpha, and IL-1 beta significantly decreased proliferation. Transforming growth factor beta induced a biphasic response in proliferation in DU-145 and PC-3 cells and produced no response on LNCaP cells. Increased cell chemotaxis occurred in the presence of IGF-I and IGF-II, and decreased cell chemotaxis occurred with the addition of TNF-alpha and IL-1 beta. These data indicate that growth factors produced by bone cells alter prostate carcinoma cell proliferation and chemotaxis and suggest that modulations of the production of these factors may be a potential therapeutic intervention in deterring the metastasis of prostate carcinoma to bone.

Cortical bone resorption during exercise is interleukin-6 genotype-dependent

“…Indeed, it would also be interesting to determine whether such alterations in skeletal structure are also associated with measurable differences in other aspects of physical performance. However, the implied role of IL-6 across different age ranges (Fishman et al 1998;Scheidt-Nave et al 2001), sexes (Ferrari et al 2001;Tsingotjidou et al 2001) and diverse disease states (Fishman et al 1998;Hyams et al 1997;Marenda and Aufdemorte 1995;Paule et al 1998;Ritchie et al 1997;Roodman 1995;Schulte et al 2000;Tsingotjidou et al 2001) do suggest a fundamental role for IL-6 in driving bone resorption. If confirmed, such data would suggest potential new therapeutic roles for novel IL-6 antagonists in the management of bone disease.…”

Insulin-Like Growth Factor (IGF) family and prostate cancer

“…that either directly affect osteoblast functions or modify the bone matrix or microenvironment. Osteoblasts also secrete factors that facilitate progression of PCa in bone [137,138].…”

Osteoblasts induce prostate cancer proliferation and PSA expression through interleukin-6-mediated activation of the androgen receptor

“…There are many factors derived from the bone microenvironment that may promote establishment and progression of CaP cells in bone [reviewed in 4] and contribute to cross-talk between the CaP cells and the bone microenvironment [reviewed in 5]. Evidence in support of the possibility that bone-derived factors contribute to the development of CaP metastases has been derived from studies in which conditioned media from bone cultures induced cancer cell growth of a variety of tumor cell lines [6][7][8]. Several specific bone-derived factors have been demonstrated to stimulate CaP cell growth in vitro, including insulin-like growth factor-1 and 2 (IGF-1 and IGF-2) [9][10], fibroblast growth factor-8 (FGF-8) [8], stromal-derived factor-1 (SDF-1) [11] and osteonectin [12][13].…”