Parathyroid hormone-related protein and bone metastases

Abstract

Parathyroid hormone‐related protein (PTH‐rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH‐rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH‐rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastatic to bone expresses PTH‐rP in >90% of cases, compared with only 17% of metastasis to nonbone sites. These observations suggest that PTH‐rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor‐β (TGF‐β), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH‐rP expression and tumor cell growth. To investigate the role of PTH‐rP in the pathophysiology of breast carcinoma metastasis to bone, the human breast carcinoma cell line MDA‐MB‐231 was studied in a murine model of human breast carcinoma metastasis to bone. A series of experiments were performed in which 1) PTH‐rP secretion was altered, 2) the effects of PTH‐rP were neutralized, or 3) the responsiveness to TGF‐β was abolished in MDA‐MB‐231 cells. Cultured MDA‐MB‐231 cells secreted low amounts of PTH‐rP that increased fivefold in response to TGF‐β. Tumor cells inoculated into the left cardiac ventricle of nude mice caused osteolytic metastasis similar to that observed in humans with breast carcinoma. When PTH‐rP was overexpressed in the tumor cells, bone metastases were increased. MDA‐MB‐231 cells transfected with the cDNA for human preproPTH‐rP secreted a tenfold greater amount of PTH‐rP and caused significantly greater bone metastases when inoculated into the left cardiac ventricle of female nude mice compared with parental cells. In contrast, when the biologic effects of PTH‐rP were neutralized or its production was suppressed, such metastases were decreased. Treatment of mice with a neutralizing monoclonal antibody to human PTH‐rP resulted in a decrease in the development and progression of bone metastasis due to the parental MDA‐MB‐231 cells. Similar results were observed when mice were treated with dexamethasone, a potent glucocorticoid that suppresses production of PTH‐rP by the MDA‐MB‐231 cells in vitro. The role of bone‐derived TGF‐β in the development and progression of bone metastasis was studied by transfecting MDA‐MB‐231 cells with a cDNA encoding a TGF‐β type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF‐β. Stable clones expressing this mutant receptor (MDA/TβRIIΔcyt) did not increase PTH‐rP secretion in response to TGF‐β stimulation compared with controls of untransfected MDA‐MB‐231 or those transfected with the empty vector. Mice inoculated into the left cardiac ventricle with MDA/TβRIIΔcyt had fewer and smaller bone metastases...

A role for Runx2 in normal mammary gland and breast cancer bone metastasis

“…Expression of Runx2 target genes appears to confer features of an osteoblast-like phenotype upon breast cancer cells, a phenomenon termed osteomimicry [Barnes et al, 2003]. The first clue pointing to a role for Runx2 in bone metastases was the observation that the Runx2 target gene, collagenase-3, was constitutively expressed in the human breast cancer cells MDA-MB-231 [Selvamurugan and Partridge, 2000]; these cells are highly metastatic and form osteolytic lesions when injected into mice [Guise, 1997]. Collagenase-3 is a member of the family of matrix metalloproteinases (MMPs) which are often expressed by metastatic cancers and contribute to their ability to invade tissues [reviewed in Ala-aho and Kahari, 2005], it is a known in vivo target gene of Runx2 in bone and further analyses have demonstrated that Runx2 does indeed regulate collagenase-3 expression in MDA-MB-231 cells [Jimenez et al, 1999;Selvamurugan et al, 2004].…”

High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects

“…A protein produced by tumor cells, designated as parathyroid hormone-related protein (PTH-rP), is mainly responsible for osteoclast cell activation (23). This is a 175-to 177-aa protein that is mainly produced by tumor cells in the bone microenvironment under promotion by TGF-␤ and other cytokines, whose levels are normally very high in the bone matrix (24,25).…”

Identification of parathyroid hormone-related protein-derived peptides immunogenic in human histocompatibility leukocyte antigen-A24+ prostate cancer patients

“…These lines of evidence indicate that PTHrP could be a good target for the development of specific immunotherapies against metastatic prostate cancer. Indeed, PTHrP 59 -68 and PTHrP 165 -173 peptides have been reported to be candidates for such specific immunotherapy of HLA-A2 þ prostate cancer patients (Guise, 1997;Francini et al, 2002). In this study, we identified new PTHrP peptides that have the potential to generate prostate cancerspecific CTLs in HLA-A24 þ prostate cancer patients, in order to extend the possibility of PTHrP peptide-based anticancer vaccine.…”

“…In parathyroid cells, a high extracellular calcium concentration inhibits parathyroid hormone (PTH) secretion and the proliferation of parathyroid cells as a result of negative feedback regulation, whereas it evokes further PTHrP secretion and promotes worsening bone resorption (Sanders et al, 2001). Therefore, PTHrP has been considered to be responsible for the hypercalcemia associated with malignancy (Guise, 1997). In addition, prostate cancers have been reported to produce PTHrP (Francini et al, 2002).…”