Direct evidence that PTHrP expression promotes prostate cancer progression in bone

doi:10.1016/j.bbrc.2004.11.162

Biochemical and Biophysical Research Communications

Volume 327, Issue 2, 11 February 2005, Pages 468-472

https://doi.org/10.1016/j.bbrc.2004.11.162 Get rights and content

Abstract

Parathyroid hormone-related protein (PTHrP) is an oncoprotein that is expressed in many malignancies as well as normal tissues. At essentially every site of expression, PTHrP regulates cell growth and proliferation. We and other investigators have previously reported that PTHrP is widely expressed by prostate cancer. For this tumor, there are substantial in vitro and correlative data that PTHrP expression regulates the progression of the tumor, especially in bone, but little direct data. We studied the effects of PTHrP expression on prostate cancer behavior directly in a mouse model of human prostate cancer cells that were transfected to express different forms of the polypeptide and then injected intraskeletally. Skeletal progression of the prostate cancer cells was evaluated radiologically and by measurement of serum tumor markers. PTHrP transfection converted a non-invasive cell line into one that progressed in the skeleton: Injection of the PTHrP transfected cells resulted in greater tumor progression in bone when compared to non-transfected cells, and this effect was also influenced by non-amino terminal peptides of PTHrP. Serum measurements of PTHrP, IL-6, IL-8, and calcium reflected tumor burden. Our experiments provide direct in vivo evidence that PTHrP expression results in the skeletal progression of prostate cancer cells.

Section snippets

Materials and methods

Cells. The DU 145 and PC-3 human prostate cancer cell lines [6], [7] were obtained from American Type Culture Collection (Manassas, VA) and grown in monolayer in RPMI 1640 media (MediaTech, Herndon, VA) supplemented with 10% fetal bovine serum (Gemini Bio Products, Woodland, CA) at 37 °C in a humidified incubator with 95% air, 5% CO₂. The DU 145 cell line was selected because it has a low constitutive PTHrP expression and does not grow or metastasize well in mouse tumor models, in contrast to

Results

We studied the effects of PTHrP expression on the skeletal progression of prostate cancer cells with stable PTHrP transformants of the non-invasive DU 145 prostate cancer cell line that does not express substantial amounts of PTHrP, especially when compared to the invasive PC-3 cells, which robustly express PTHrP [6], [7]. The PTHrP expression plasmids used in this study were human prepro-PTHrP1–173 and prepro-PTHrP1–87, absent in the carboxy terminal moieties of full-length PTHrP [7].

Discussion

While the most widely studied effects of PTHrP have been of its amino terminal peptide, which signals through the same receptor as PTH, there is accumulating evidence that non-amino terminal peptides of PTHrP can exert biological effects [1], [12], [13]. For example, PTHrP107–141 has in some studies been reported to inhibit osteoclast function [14]; and we have recently demonstrated that PTHrP140–173 has growth-regulatory actions [13]. These bioactive peptides can be derived through processing

Acknowledgments

The authors gratefully acknowledge expert technical assistance in these studies provided by M.Yang, P. Jiang, C. Chalberg, K. Smith, and S. Tu. This work was supported by a VA Merit Review grant, the PC-REF, NIH Grants (DK-60586, AR47347), and the DOD Prostate Cancer Research Program Award No. DAMD17-01-1-0016.

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^☆: Abbreviations: PTHrP, parathyroid hormone-related protein; SCID, severe combined immunodeficiency; IL, interleukin; PBS, phosphate-buffered saline; i.v., intravenous; SEM, standard error of the mean.

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Direct evidence that PTHrP expression promotes prostate cancer progression in bone☆

Abstract

Section snippets

Materials and methods

Results

Discussion

Acknowledgments

Hum. Pathol.

Urology

Urology

Regul. Pept.

Endocrinol. Metab. Clin. North Am.

Prostate carcinoma: production of bioactive factors

Cancer

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

Int. J. Cancer

Immunohistochemical localization of parathyroid hormone-related protein in human prostate cancer

Cancer Res.

Animal models of prostate cancer

PTHrP induces IL-8 production by prostate cancer cells via a novel intracrine mechanism not mediated by its classical nuclear localizing sequence

Cancer Res.