Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP)

Abstract

Parathyroid hormone related protein (PTHrP) is a well characterized tumor derived product that also has integral functions in normal development and homeostasis. PTHrP is produced by virtually all tumor types that metastasize to bone and numerous studies have demonstrated a correlation between PTHrP expression and skeletal localization of tumors. PTHrP has prominent effects in bone via its interaction with the PTH-1 receptor on osteoblastic cells. Through indirect means, PTHrP supports osteoclastogenesis by upregulating the receptor activator of NFkappaB ligand (RANKL) in osteoblasts. PTHrP also regulates osteoblast proliferation and differentiation in manners that are temporal and dose dependent. Bone turnover has been implicated in the localization of tumors to bone and PTHrP increases bone turnover. Bone turnover results in the release of growth factors such as TGFbeta and minerals such as calcium, both of which impact tumor cell growth and contribute to continued PTHrP production. PTHrP also has anabolic properties and could be in part responsible for osteoblastic type reactions in prostate cancer. Finally, emerging roles of PTH and PTHrP in the support of hematopoietic stem cell development in the bone marrow microenvironment suggest that an interaction between hematopoietic cells and tumor cells warrants further investigation.

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

“…Expression of the ligand trap significantly inhibited the ability of breast cancer cells to grow effectively in the bone and suppressed TGF-b-induced expression of PTHrP and IL-11, two osteoclastic factors that are important for the formation of breast cancer bone metastases (Manolagas, 1995;Yin et al, 1999;Sotiriou et al, 2001;Kakonen et al, 2002;Kang et al, 2003Kang et al, , 2005Deckers et al, 2006;Liao and McCauley, 2006). These results are consistent with the observation that a dominant negative TbRII or a TbRI inhibitor impaired the ability of breast cancer cells to metastasize to bone (Yin et al, 1999 that an increase in the local concentration of the ligand trap would be achieved as Fc:TbRII(ECD)-producing tumors progressively grow in the bone.…”

PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling

“…PTHrP has been detected in many tumors, particularly breast and prostate [2]. In this study, we first examined the levels of PTHrP by RT-PCR in five independent human OSCC cell lines: SAS, Ca9-22, HSC-2, HSC-3, and HSC-4.…”

PTHrP Produced by Myeloma Plasma Cells Regulates Their Survival and Pro-Osteoclast Activity For Bone Disease Progression

“…(9)(10)(11)(12) Subsequent studies have described its functional effects through either paracrine or autocrine cell stimulation by tumors with no skeleton involvement and even by several normal tissues. (13)(14)(15) An intracrine effect of PTHrP has been also postulated in breast cancer to improve the nucleocytoplasmic trafficking that accelerates cell cycle progression, RNA transcription, and transport. (16)(17)(18) Structurally, PTHrP contains three functional domains, namely NH 2 -terminal, mid-region, and COOH-terminal fragments.…”

“…(22) The functional role of PTHrP fragments in human pathophysiology has been intensively investigated and their generation by posttranslational proteolysis of members of the subtilisin family, has been definitely assessed. (23)(24)(25) Tumors producing skeletal metastases are usually associated with high PTHrP activity that apparently correlates with poor prognosis in both breast and prostate cancers, (13) although a survival advantage has been unexpectedly described in female patients with lung adenocarcinoma and serum elevation of PTHrP. (26) Nevertheless, the role of PTHrP on cancer growth has been definitely confirmed by demonstrating that its suppression, by either neutralizing antibodies in MDA-MB-231 breast cancer cells or by antisense oligonucleotides in mouse models, restrains tumor progression, resulting in marked reduction of tumor size.…”