Parathyroid hormone related-protein promotes epithelial-to-mesenchymal transition in prostate cancer.

Parathyroid hormone-related protein (PTHrP) possesses a variety of physiological and developmental functions and is also known to facilitate the progression of many common cancers, notably their skeletal invasion, primarily by increasing bone resorption. The purpose of this study was to determine whether PTHrP could promote epithelial-to-mesenchymal transition (EMT), a process implicated in cancer stem cells that is critically involved in cancer invasion and metastasis. EMT was observed in DU 145 prostate cancer cells stably overexpressing either the 1-141 or 1-173 isoform of PTHrP, where there was upregulation of Snail and vimentin and downregulation of E-cadherin relative to parental DU 145.

Deletion of the gene encoding calcitonin and calcitonin gene-related peptide α does not affect the outcome of severe infection in mice.

Procalcitonin (PCT) is expressed in nonthryoidal tissues of humans during severe infections. Serum PCT levels are measured to diagnose and guide therapy, and there is some evidence that PCT may also contribute to the pathogenesis of sepsis. We tested whether disruption of the gene encoding PCT in mice affected the course of sepsis.

Hypercalcemia in disseminated coccidioidomycosis: expression of parathyroid hormone-related peptide is characteristic of granulomatous inflammation.

Background: Hypercalcemia is an uncommon complication of disseminated granulomatous infections. The pathogenesis of hypercalcemia associated with infection is not clear.

Methods: We investigated a case of disseminated coccidioidomycosis with hypercalcemia.

PTH/PTHrP and vitamin D control antimicrobial peptide expression and susceptibility to bacterial skin infection.

The production of antimicrobial peptides is essential for protection against a wide variety of microbial pathogens and plays an important role in the pathogenesis of several diseases. The mechanisms responsible for expression of antimicrobial peptides are incompletely understood, but a role for vitamin D as a transcriptional inducer of the antimicrobial peptide cathelicidin has been proposed. We show that 1,25-dihydroxyvitamin D(3) (1,25-D3) acts together with parathyroid hormone (PTH), or the shared amino-terminal domain of PTH-related peptide (PTHrP), to synergistically increase cathelicidin and immune defense.

Prognostic implications of parathyroid hormone-related protein in males and females with non--small-cell lung cancer.

Background: Non-small-cell lung carcinoma immunoreactivity for parathyroid hormone-related protein has been associated with increased survival in female patients but not in male patients. The current investigation attempted to substantiate this finding in 2 new patient groups.

Methods: Patients were divided into groups with and without immunoreactivity for a carboxyl-terminal parathyroid hormone-related protein epitope assessed in deparaffinized sections by a blinded observer.

Knockdown of the β(1) integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis.

To address the role of β(1) integrins in pancreatic cancer progression, we stably knocked down β(1) integrin subunit expression in human FG-RFP pancreatic cancer cells using lentiviral-based RNA interference. We then examined the effects of β(1) integrin subunit knockdown on pancreatic cancer cell adhesion, migration and proliferation on tumor microenvironment-specific extracellular matrix proteins in vitro and on tumor progression in vivo using a clinically relevant fluorescent orthotopic mouse model of pancreatic cancer. Knockdown of the β(1) integrin subunit inhibited cell adhesion, migration and proliferation on types I and IV collagen, fibronectin and laminin in vitro.

Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with multiple endocrine neoplasia type 1.

We report a patient with multiple endocrine neoplasia type 1 presenting with elevation of parathyroid hormone-related protein (PTHrP) from a metastatic pancreatic neuroendocrine tumor (PNET), and parathyroid hormone (PTH) from primary hyperparathyroidism, resulting in severe hypercalcemia. Parathyroid hormone-related protein production by the PNET was confirmed by immunohistochemical analysis. Hypercalcemia and elevated PTHrP improved markedly with hepatic artery chemoembolization of liver metastasis.

PTHrP stimulates prostate cancer cell growth and upregulates aldo-keto reductase 1C3.

The aim of the study was to demonstrate the role of parathyroid hormone related protein (PTHrP) in stimulating aldo-keto reductase (AKR) 1C3 expression in prostate cancer (CaP) cells. CaP cell proliferation and resistance to apoptosis was increased by PTHrP transfection. Conversely, reducing AKR1C3 expression by siRNA decreased cell proliferation.

Combinatorial library discovery of small molecule inhibitors of lung cancer proliferation and parathyroid hormone-related protein expression.

PTHrP (parathyroid hormone-related protein) is abnormally expressed in a substantial majority of lung cancers, especially non-small cell lung cancers, and plays a key role in tumor progression. Thus, this oncoprotein could be a target for treating patients with lung cancer. This study screened combinatorial libraries of heterocyclic amines for inhibitory effects on PTHrP expression and cell proliferation.

Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma.

Parathyroid hormone-related protein (PTHrP), a paraneoplastic protein expressed by two-thirds of human non-small cell lung cancers, has been reported to slow progression of lung carcinomas in mouse models and to lengthen survival of patients with lung cancer. This study investigated the effects of ectopic expression of PTHrP on proliferation and cell cycle progression of two human lung adenocarcinoma cell lines that are normally PTHrP negative. Stable transfection with PTHrP decreased H1944 cell DNA synthesis, measured by thymidine incorporation, bromodeoxyuridine uptake, and MTT proliferation assay.

Parathyroid hormone-related protein varies with sex and androgen status in nonsmall cell lung cancer.

Background: In nonsmall cell lung cancer, tumor parathyroid hormone-related protein (PTHrP) expression predicts longer survival in women but not in men. To explain the sex-dependent survival effect, the authors proposed that hormonal influences decrease PTHrP in men versus women, that PTHrP inhibits tumor growth, and that the effect is greater in women than in men. The objectives of this study were to compare lung carcinoma PTHrP expression and carcinoma growth in male and female mice and to determine whether gonadal steroids regulate PTHrP in lung cancer cells.

Incidental finding of metastatic papillary thyroid carcinoma in a patient with primary hyperparathyroidism.

Objective: To report on the management of a patient with the rare concurrence of primary hyperparathyroidism and incidentally found metastatic papillary thyroid carcinoma in an adjacent lymph node.

Methods: We present a case report, including scintigraphic and histologic documentation, and a summary of the related literature.

Results: Primary hyperparathyroidism with concomitant occurrence of nonmedullary thyroid carcinoma is rare, occurring in less than 4% of patients.

Integrin-mediated laminin-1 adhesion upregulates CXCR4 and IL-8 expression in pancreatic cancer cells.

Background: We have shown recently that alpha(2)beta(1) integrin-mediated type I collagen adhesion promotes a more malignant phenotype in pancreatic cancer cell lines than other extracellular matrix (ECM) proteins. MiaPaCa-2 cells, by contrast, do not express collagen-binding integrins, but are metastatic in our orthotopic mouse model and migrate maximally on laminin-1 (Ln-1). It has also been shown that CXCR4 and IL-8 expression correlates directly with metastasis in pancreatic cancer in vivo.

Congenital craniopharyngioma and hypercalcemia induced by parathyroid hormone-related protein.

Objective: To report a case of congenital craniopharyngioma and parathyroid hormone-related protein (PTHrP)-associated humoral hypercalcemia.

Methods: Details of this unusual case are reviewed, from detection of fetal hydrocephalus and a brain tumor, through cesarean delivery at 36 weeks of gestation, to subsequent laboratory studies, management, and confirmation of the diagnosis.

Results: Although PTHrP has been well documented as a cause of humoral hypercalcemia of malignancy (HHM) in adult patients with cancer, HHM is uncommon in children.

Causes of hypercalcemia in a population of military veterans in the United States.

Objective: To determine the various causes of hypercalcemia in a population of US veterans at the San Diego Veterans Affairs Medical Center.

Methods: A retrospective analysis of medical records was performed on 212 US veterans encountered between 1998 and 2002 with serum calcium measurements between 10.5 and 10.

Type I collagen and divalent cation shifts disrupt cell-cell adhesion, increase migration, and decrease PTHrP, IL-6, and IL-8 expression in pancreatic cancer cells.

Background: We have shown in FG pancreatic cancer cells that alpha2beta1 integrin-mediated type I collagen adhesion decreases parathyroid hormone-related protein (PTHrP), interleukin-6 (IL-6), and interleukin-8 (IL-8) expression, decreases the localization of E-cadherin and beta-catenin in cell-cell contacts, increases cell migration, and increases glycogen synthase kinase 3 (GSK3) and protein kinase B (PKB/Akt) phosphorylation states relative to alpha5beta1 integrin-mediated fibronectin (Fn) adhesion.

Aim Of The Study: To extend our observations in FG cells to other pancreatic cancer cell lines, and to determine whether E-cadherin-mediated cell-cell adhesion and its downstream effectors were functionally involved in the ECM-mediated regulation of PTHrP, IL-6, and IL-8.

Methods: We used standard biochemical techniques to determine ECM-specific differences in E-cadherin and beta-catenin localization, GSK3 and PKB/Akt phosphorylation, haptokinetic cell migration, and cytokine expression in pancreatic cancer cells.

The bisphosphonate olpadronate inhibits skeletal prostate cancer progression in a green fluorescent protein nude mouse model.

Purpose: Metastatic bone disease is one of the major causes of morbidity and mortality in prostate cancer patients. Bisphosphonates are currently used to inhibit bone resorption and reduce tumor-induced skeletal complications. More effective bisphosphonates would enhance their clinical value.

Identification of DU 145 prostate cancer cell proteins that bind to the carboxy-terminal peptide of human PTHrP in vitro.

Peptides spanning the range of human parathyroid hormone-related protein (PTHrP) have been shown to bind heat shock protein-70 expressed on the surface of cancer cells with cytoprotective consequences in vitro. The present study focused on identification of intracellular proteins that interact with the carboxy-terminal peptide of human PTHrP. Using affinity chromatography, we applied extracts of DU 145 prostate cancer cells over PTHrP (140-173)-Sepharose and eluted with 8 M urea.

Sex-specific survival advantage with parathyroid hormone-related protein in non-small cell lung carcinoma patients.

Purpose: Parathyroid hormone-related protein (PTHrP) is commonly expressed in non-small cell lung carcinomas (NSCLC). Expression of the protein could have implications for progression of the disease because it regulates cancer cell growth, apoptosis, and angiogenesis. However, its relationship with survival has not been evaluated in a large-scale investigation.

A carboxyl leucine-rich region of parathyroid hormone-related protein is critical for nuclear export.

PTHrP is an oncofetal protein with distinct proliferative and antiapoptotic roles that are affected by nucleocytoplasmic shuttling. The protein's nuclear export is sensitive to leptomycin B, consistent with a chromosome region maintenance protein 1-dependent pathway. We determined that the 109-139 region of PTHrP was involved in its nuclear export by demonstrating that a C-terminal truncation mutant, residues 1-108, exports at a reduced rate, compared with the wild-type 139 amino acid isoform.

Hypercalcemia and local production of parathyroid hormone-related protein by a perisellar rhabdomyosarcoma after remote pituitary irradiation.

Objective: To describe a case of metastatic rhabdomyosarcoma originating from the sphenoid sinus in a patient previously treated with conventional irradiation for a prolactinoma, presenting as hypercalcemia in the setting of a normal level of serum parathyroid hormone-related protein (PTHrP).

Methods: We report the case of a patient who underwent remote pituitary irradiation for a prolactinoma and then presented decades later with hypercalcemia of unknown cause. His clinical course, the initial biochemical and radiologic investigations, and the results of examination of pathology specimens are reviewed.