Over‐production of parathyroid hormone–related peptide results in increased osteolytic skeletal metastasis by prostate cancer cells In vivo

Abstract

Prostate carcinoma is one of the most common malignancies affecting males, resulting in a high rate of morbidity and mortality. This hormone-dependent malignancy is characteristically associated with a high incidence of osteoblastic skeletal lesions. However, osteolytic lesions invariably accompany blastic ones. In the current study, we assessed the role of parathyroid hormone-related peptide (PTHRP), a potent bone-resorbing agent, in contributing to bone breakdown and prostatic skeletal metastasis using a syngeneic rat prostate cancer model. The full-length cDNA encoding rat PTHRP was subcloned as a Hind III insert in the sense orientation into the mammalian expression vector pRc-CMV to generate the expression vector pRc-PTHRP-S. Both control and experimental plasmids were stably transfected into low PTHRPproducing Dunning R3227, Mat Ly Lu rat prostate cancer cells. Prostatic cancer has a high propensity to metastasize to the skeleton, and skeletal metastatic disease is a major cause of morbidity (Chiarodo et al., 1991). Osteoblastic lesions are characteristic of the bone disease caused by prostate cancer, and indeed, prostate cancer is one of the most common cancers associated with osteoblastic bone disease. Several potential mediators of the osteoblastic response in bone have been described, including transforming growth factor beta (TGF-␤), fibroblast growth factor (FGF), bone morphogenetic protein (BMP) and the NH 2 -terminal region of urokinase (Harris et al., 1994;Rabbani et al., 1990Rabbani et al., , 1992. Many, if not all, skeletal lesions of prostate cancer, however, also include an osteolytic component (Franks, 1973). Both histological and biochemical evidence support the presence of osteolysis in association with prostate cancer metastases to bone; nevertheless, this component of the disease has received relatively little attention (Franks, 1973;Takeuchi et al., 1996). The most common skeletal response to cancer metastases in general is osteolysis, and the mechanisms underlying this response are now beginning to be defined. The mediators of osteolysis appear to include cytokines, growth factors and possibly prostaglandins released either by invading tumor cells or by host cells in bone in response to invading tumor cells (Jilka et al., 1992;Bonjour and Rizzoli, 1989;Francini et al., 1993).Parathyroid hormone-related peptide (PTHRP) is a moiety which was first discovered as a mediator of hypercalcemia associated with malignancy (Henderson et al., 1989;Suva et al., 1987;Asadi et al., 1996). Three PTHRP isoforms exist in humans, which are 139, 141 and 173 amino acids in length. All isoforms share homology at the NH 2 terminus with the NH 2 region of parathyroid hormone (PTH) (Moseley et al., 1987; Steward et al, 1987;Strewler et al., 1987;Rabbani et al., 1986). This homology facilitates interaction with a common PTH/PTHRP receptor and serves as the molecular basis for similar biological actions of PTH and PTHRP (Jüeppner et al., 1991;Abou-Samra et al., 1992). Included in these actions is the capacity to...

Interactions between microenvironment and cancer cells in two animal models of bone metastasis

“…Tumour cells produce a variety of soluble factors (PTHrP, TGF-b, IGF, endothelin-1y) that are employed as a paracrine communication system with surrounding cells or as an autocrine regulation system (Guise and Mundy, 1998;Guise et al, 2003;Lee et al, 2003). W256 and MatLyLu cells are unable to resorb bone by themselves and have been reported to produce high levels of PTHrP, which promotes osteoclastogenesis (Rizzoli and Fleisch, 1987;Rabbani et al, 1999).…”

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

“…The role of PTHrP in mediating the metastasis of breast and prostate cancer cells to the bone has been firmly established [43][44][45][46]. Expression of PTHrP by breast cancer bone metastases is higher than at the primary site or by non-bone metastases [47][48][49].…”

PTHrP increases xenograft growth and promotes integrin α6β4 expression and Akt activation in colon cancer

“…Multiple studies demonstrate that PTHrP plays a major role in tumors that metastasize to the bone, such as breast and prostate cancer [26,27]. However, there is increasing evidence that PTHrP also plays a role in cancers that metastasize to other regions of the body, such as colon tumors, which show a preference for the liver [2].…”