Loss of expression of bone morphogenetic protein receptor type II in human prostate cancer cells

Abstract

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily and signal through a number of membrane receptors. We have previously demonstrated that the loss of expression of BMP receptors (BMPRs) type IA, -IB, and -II (BMP-RIA, -RIB, and -RII) correlates with Gleason score in prostate cancer patients. To evaluate the prognostic value of this observation, we used immunohistochemistry to investigate the expression of BMPRs in association with disease progression in 60 patients. The results demonstrated a significant association between the loss of expression of the three BMPRs and Gleason score and clinical stage. However, only the loss of expression of BMP-RII showed a statistically significant association with 5-year survival rate (P<0.05) and biochemical recurrence-free rate following radical prostatectomy (P<0.005). To elucidate the effect of an abnormal BMP signaling in prostate cancer cells, we transfected dominant-negative BMP-RII (BMP-RIIDN) into the human prostate cancer cell line, PC3M. When a stable clone overexpressing BMP-RIIDN was inoculated subcutaneously into nude mice, the tumor growth rate was approximately 10 times that of control and parental cell line. These observations, taken together, indicate that the loss of BMP-RII expression as measured by immunohistochemistry may be a prognostic marker in prostate cancer patients, and that the loss of BMP-RII function may result in increased tumorigenicity in human prostate cancer cells.

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

“…Bone morphogenetic proteins are expressed in various carcinoma cell lines of gastric, ovarian, prostate, pancreatic and breast origin (Hatakeyama et al, 1993;Kim et al, 2000;Langenfeld et al, 2003). Studies using a variety of tumor systems revealed that BMP signaling produces a complex set of effects in cancer, in which they can be either protumorigenic or antitumorigenic.…”

“…BMPs are expressed in a variety of human carcinoma cell lines (Hatakeyama et al, 1993;Kim et al, 2000;Langenfeld et al, 2003), and mutations of the human ACVR2 gene, encoding ALK2, have been reported to be responsible for the development of juvenile polyposis in some patients (Howe et al, 2001;Haramis et al, 2004). BMP signaling has also been shown to inhibit tumorigenesis of several tumor types, including brain tumors, basal cell carcinomas of the skin and gastric cancer (Piccirillo et al, 2006;Sneddon et al, 2006;Bleuming et al, 2007).…”

Bone morphogenetic protein-2/4 and bone morphogenetic protein receptor type IA expression in metastatic and nonmetastatic oral squamous cell carcinoma

“…Hardwick et al [16] investigated the immunoexpression of BMP-2 in intestinal colon specimens of patients with familial adenomatous polyposis and observed the loss of BMP-2 expression in dysplastic areas of the microadenoma, when compared to the superficial layer of normal epithelium adjacent to the tumor that exhibited significant immunoreactivity. Kim et al [17,18] observed elevated expression of BMP receptors in normal prostatic and bladder tissue. These studies suggest that the responsiveness to BMPs and their receptors may vary among different cell types, including those of the same embryonic origin.…”

“…In metastatic OSCC specimens, expression tended to be weak in all cases analyzed. During carcinogenesis, especially in the more advanced stages of the disease, neoplastic cells commonly lose their responsiveness to BMPs, either due to the loss of expression of their receptors or to the increased synthesis of BMP inhibitors such as noggin [4,17,18,24]. The loss of expression of BMP receptors, especially BMPR-IA, is expected in many human cancers such as prostate, bladder, breast, and intestinal colon cancer.…”

Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

“…However, additional signalling pathways are acknowledged to play important roles in malignant disease, with the bone morphogenetic protein (BMP) signalling pathway emerging as important in multiple cancers (Nagatake et al, 1996;Tamada et al, 2001;Baldus et al, 2004;Dai et al, 2004;Kim et al, 2004). It is well recognised that the BMP signalling pathways are crucial for all stages of embryonic development, including regulation of lung development and airway branching (Weaver et al, 1999;Lu et al, 2001;Rosendahl et al, 2002).…”