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. By contrast, the opposite effect was observed in PC-3 prostate cancer cells where high levels of PTHrP were knocked-down via lentiviral siRNA transduction. Increased tumor progression was observed in PTHrP-overexpressing DU 145 cells while decreased progression was observed in PTHrP-knockdown PC-3 cells. PTHrP-overexpressing DU 145 formed larger tumors when implanted orthoptopically into nude mice and in one case resulted in spinal metastasis, an effect not observed among mice injected with parental DU 145 cells. PTHrP-overexpressing DU 145 cells also caused significant bone destruction when injected into the tibiae of nude mice, while parental DU 145 cells caused little to no destruction of bone. Together, these results suggest that PTHrP may work through EMT to promote an aggressive and metastatic phenotype in prostate cancer, a pathway of importance in cancer stem cells. Thus, continued efforts to elucidate the pathways involved in PTHrP-induced EMT as well as to develop ways to specifically target PTHrP signaling may lead to more effective therapies for prostate cancer.

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. Mice with exons 2-5 of the gene encoding calcitonin/calcitonin gene-related polypeptide α (Calca) knocked out and congenic C57BL/6J control mice were challenged with aerosolized Streptococcus pneumoniae or Pseudomonas aeruginosa, or injected intraperitoneally with S. pneumoniae. There were no significant differences in the survival of knockout and control mice in the two pneumonia models, and no significant differences in weight loss, splenic bacterial counts, or blood leukocyte levels in the peritoneal sepsis model. To verify disruption of the Calca gene in knockout mice, the absence of calcitonin in the serum of knockout mice and its presence and inducibility in control mice were confirmed. To evaluate PCT expression in nonthyroidal tissues of control mice, transcripts were measured in multiple organs. PCT transcripts were not significantly expressed in liver or spleen of control mice challenged with aerosolized P. aeruginosa or intraperitoneal endotoxin, and were expressed in lung only at low levels, even though serum IL-6 rose 3,548-fold. We conclude that mice are not an ideal loss-of-function model to test the role of PCT in the pathogenesis of sepsis because of low nonendocrine PCT expression during infection and inflammation. Nonetheless, our studies demonstrate that nonendocrine PCT expression is not necessary for adverse outcomes from 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. We used a sensitive radioimmunoassay to measure serum parathyroid hormone-related peptide (PTHrP) and a mouse monoclonal antibody to PTHrP to immunostain biopsies. RESULTS: We found elevated serum levels of PTHrP while the patient was hypercalcemic that became undetectable when serum calcium normalized. We also found that the inflammatory cells and some surrounding tissues in skin biopsies expressed PTHrP. PTHrP was expressed by all biopsied lesions of patients with coccidioidomycosis that we examined, whether localized to the lung or disseminated, but no other cases were hypercalcemic. PTHrP was also expressed by the 3 mycobacterial granulomas we examined, and in a lymph node from a patient with sarcoidosis. CONCLUSIONS: The expression of PTHrP is a property of infectious granulomas regardless of etiology or the tissue involved, suggesting that PTHrP expression is part of the normal granulomatous immune response. Hypercalcemia may result if there is disseminated infection and multiple granulomas. We propose that excess production of PTHrP is the cause of hypercalcemia in granulomatous infections.

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. Administration of PTH to mouse skin decreased susceptibility to skin infection by group A Streptococcus. Mice on dietary vitamin D(3) restriction that responded with an elevation in PTH have an increased risk of infection if they lack 1,25-D3. These results identify PTH/PTHrP as a variable that serves to compensate for inadequate vitamin D during activation of antimicrobial peptide production.

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. One group included 85 female patients with stage I lung cancer, and the second group had 48 female and 66 male patients with stage I-IV lung cancer. Survival times were compared by the log-rank test between groups separated by tumor parathyroid hormone-related protein status. RESULTS: Parathyroid hormone-related protein was present in 70%-80% of the patients, independent of sex, stage, and smoking history. In the females with stage I lung cancer, parathyroid hormone-related protein increased median survival from 25 to 60 months (P < .05). In the second group, parathyroid hormone-related protein expression increased 48-month disease-free survival of female lung cancer patients from 44% to 63% (P < .05), but had no effect in male patients. Parathyroid hormone-related protein remained a significant, independent predictor when evaluated together with other covariates by Cox multivariate regression. CONCLUSION: This study verifies that parathyroid hormone-related protein is a sex-dependent survival factor for non-small-cell lung carcinoma, that it correlates with disease-free survival, and that the association with survival holds for women with early-stage disease as well as more advanced cancer. Thus, the protein could find use as a prognostic indicator and could be a target for therapy.

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

To address the role of ß(1) integrins in pancreatic cancer progression, we stably knocked down ß(1) integrin subunit expression in human FG-RFP pancreatic cancer cells using lentiviral-based RNA interference. We then examined the effects of ß(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 ß(1) integrin subunit inhibited cell adhesion, migration and proliferation on types I and IV collagen, fibronectin and laminin in vitro. In vivo, knockdown of the ß(1) integrin subunit reduced primary tumor growth by 50% and completely inhibited spontaneously occurring metastasis. These observations indicate a critical role for the ß(1) integrin subunit in pancreatic cancer progression and metastasis in particular. Our results suggest the ß(1) integrin subunit as a therapeutic target for the treatment of pancreatic cancer, especially in the adjuvant setting to prevent metastasis of this highly aggressive cancer.

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. Thus, in multiple endocrine neoplasia type 1, correct identification of the cause of hypercalcemia as PTHrP production from a PNET or PTH production from a parathyroid tumor has important therapeutic implications.

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. Since these effects could be mediated through AKR1C3-catalyzed reductions of the PPARγ ligand, 15-DeoxyΔ(12,14)-PGJ(2), we treated the cells with prostaglandins (PG). (PG) D(2) inhibited cell proliferation, but its metabolite, 9α,11ß-PGF(2), did not effect CaP cell growth. The AKR1C family members serve as potential therapeutic targets for CaP therapy.

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. Two libraries of over 780,000 bis-cyclic thiourea and guanidine compounds each were tested in BEN lung carcinoma cells. The number of PTHrP inhibitors and the magnitude of the reduction in PTHrP were greater for thioureas. Selected lead thiourea compounds decreased cell PTHrP protein content in dose-dependent fashion, reduced relative abundance of PTHrP mRNA, decreased transcripts derived from the PTHrP P3 promoter and reduced activity of a full length PTHrP promoter luciferase construct. Similar effects on PTHrP mRNA were observed in A549 and H441 lung adenocarcinoma cells and in H727 lung carcinoid cells. However, the compounds only inhibited PTHrP protein levels in BEN cells and H727 cells. The compounds reduced the rate of cell proliferation in BEN cells and H727 cells, but not in lines that showed no inhibition of PTHrP protein. These results suggest that cyclic thiourea compounds inhibit PTHrP expression mediated by the P3 promoter, which is widely used in the majority of PTHrP-expressing cells, and that they may inhibit growth of lung cancer cells through the same mechanism. Further work will be necessary to investigate their mechanism for effects on growth of PTHrP-positive tumors in vivo.

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. A substantial fraction of PTHrP-positive cells was arrested in or slowly progressing through G1. Cyclin D2 and cyclin A2 protein levels were 60-70% lower in PTHrP-expressing cells compared with control cells (P < 0.05, N = 3 independent clones per group), while expression of p27(Kip1), a cyclin-dependent kinase inhibitor, was increased by 35 +/- 9% (mean +/- SE, P < 0.05) in the presence of PTHrP. Expression of other cyclins, including cyclins D1 and D3, and cyclin-dependent kinases was unaffected by PTHrP. PTHrP did not alter the phosphorylation state of Rb, but decreased cyclin-dependent kinase (CDK) 2-cyclin A2 complex formation. Ectopic expression of PTHrP stimulated ERK phosphorylation. In MV522 cells, PTHrP had similar effects on DNA synthesis, cyclin A2 expression, pRb levels, CDK2-cyclin A2 association, and ERK activation. In summary, PTHrP appears to slow progression of lung cancer cells into S phase, possibly by decreasing activation of CDK2. Slower cancer cell proliferation could contribute to slower tumor progression and increased survival of patients with PTHrP-positive lung cancer.

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. We report a case of a 53-year-old woman with no prior history of endocrine disease with primary hyperparathyroidism and an incidental finding of a concurrent thyroid carcinoma. In this patient, technetium 99m scintigraphy revealed a parathyroid adenoma beneath the inferior pole of the left thyroid bed. Parathyroidectomy was performed successfully with no complications. The final pathology examination showed a large parathyroid adenoma with an incidental finding of a small adjacent lymph node containing metastatic papillary thyroid carcinoma. The patient subsequently underwent total thyroidectomy, and the pathology evaluation revealed papillary thyroid carcinoma, follicular variant. CONCLUSION: To our knowledge, this case of concomitant primary hyperparathyroidism and papillary thyroid cancer is unique in the way in which the diagnosis of metastatic papillary thyroid cancer was made. The presence of parathyroid adenoma should not exclude the diagnosis of thyroid carcinoma; therefore, careful thyroid evaluation should be considered for all patients with primary hyperparathyroidism.

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. METHODS: Tumor PTHrP content was measured by immunoassay, and tumor burden was assessed with multiple measures in BEN squamous cell orthotopic lung carcinomas in athymic mice. In addition, lung adenocarcinoma PTHrP messenger RNA (mRNA) values determined by microarray analyses were compared between men and women. Cultured lung cancer cells were assayed for PTHrP after treatment with estradiol or R1881, a synthetic androgen. RESULTS: Lung carcinomas contained approximately 3 times more PTHrP in female mice than in male mice. Similarly, levels of PTHrP mRNA were significantly greater in adenocarcinomas from patients who were women than from patients who were men. Male mice had greater tumor burden than female mice. Androgen treatment reduced PTHrP in 3 lung cancer lines. Estradiol had no effect. Testosterone treatment also reduced lung carcinoma PTHrP in female mice. CONCLUSIONS: Lung carcinomas in females expressed more PTHrP than in males possibly because of negative regulation by androgens in males. Female mice with higher tumor PTHrP content had significantly less tumor burden than male mice, supporting the hypothesis that PTHrP inhibits tumor growth.

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. We therefore examined the potential of the ECM to regulate CXCR4 and IL-8 expression in pancreatic cancer cells. METHODS: We cultured 8 pancreatic cancer cell lines on fibronectin (Fn), types I and IV collagen, Ln-1 and vitronectin (Vn), and examined cell lysates for CXCR4 by immunoblotting and media for IL-8 by ELISA. We also conducted cell migration assays with stromal-derived factor-1 (SDF-1) as the chemoattractant to examine integrin-binding specificity and CXCR4 function. RESULTS: All cell lines expressed CXCR4 protein. MiaPaCa-2 cell growth on Ln-1 increased significantly CXCR4 and IL-8 expression relative to other ECM proteins. Migration inhibition studies showed that both the alpha(6)beta(1) and alpha(3)beta(1) integrins mediate MiaPaCa-2 migration on Ln-1. Growth studies showed further that CXCR4 expression on Ln-1 was mediated by the alpha(6)beta(1) integrin whereas IL-8 expression was mediated by both the alpha(6)beta(1) and alpha(3)beta(1) integrins. The expression of functional CXCR4 was also shown in migration assays, where SDF-1 significantly increased pancreatic cancer cell chemotaxis on Ln-1. CONCLUSIONS: These data indicate that integrin-mediated Ln-1 adhesion upregulates CXCR4 and IL-8 expression and may play a mechanistic role in pancreatic cancer metastases.

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. In addition, HHM has rarely been ascribed to nonmalignant tumors. To the best of our knowledge, we report the first case of a neonate with congenital craniopharyngioma and refractory hypercalcemia (peak ionized calcium level of 1.92 mmol/L; normal, 1.05 to 1.3) attributed to an elevated PTHrP value of 8.6 pmol/L (normal, less than 4.7). Intact parathyroid hormone was appropriately undetectable (less than 10 pg/mL; normal, 15 to 65). Despite calcitonin treatment, the hypercalcemia persisted. Although pamidronate infusion stabilized the serum calcium level, the baby did not survive. CONCLUSION: The diagnosis of craniopharyngioma was confirmed at autopsy, and immunohistochemical studies substantiated that the craniopharyngioma produced PTHrP.

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 10.9 mg/dL on multiple readings or 11.0 mg/dL (or greater) on any single determination. Data were collected from the clinical records for each patient and used to determine the cause of each patient's hypercalcemia. Patients undergoing hemodialysis were excluded from this study. RESULTS: The study population consisted of 201 men (95%) and 11 women (5%), with a median age of 63 years (range, 25 to 95). Of the 212 patients, 59 (28%) had a diagnosis of malignant disease, 38 (18%) had primary hyperparathyroidism, and 114 (54%) had hypercalcemia due to a range of other causes. The mean total serum calcium concentration for all patients in this study was 11.69 mg/dL. Lung carcinoma was the most prevalent malignant condition (in 17 patients or 29% of those with cancer). A single parathyroid adenoma (in 20 of 22 patients who underwent surgical intervention) accounted for the majority of cases of primary hyperparathyroidism. Among the other identified causes of hypercalcemia, acute renal failure was the most common (in 37 patients or 17% of all patients). In 37 patients, no specific cause for the hypercalcemia was identified. CONCLUSION: To our knowledge, this is the first study to focus on hypercalcemia within the US veterans population. Although the 2 most common causes of hypercalcemia, hyperparathyroidism and malignant disease, were represented in this study, the majority of cases of hypercalcemia in this population of US veterans related to other etiologic factors.

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. EXPERIMENTAL DESIGN: We tested several bisphosphonates in a green fluorescent protein (GFP)-expressing human prostate cancer nude mouse model. The in vivo effects of four bisphosphonates, including pamidronate, etidronic acid, and olpadronate, on bone tumor burden in mice intratibially inoculated with PC-3-GFP human prostate cancer cells were visualized by whole-body fluorescence imaging and X-ray. RESULTS: The PC-3-GFP cells produced extensive bone lesions when injected into the tibia of immunocompromised mice. The skeletal progression of the PC-3-GFP cell growth was monitored by GFP fluorescence and the bone destruction was evaluated by X-ray. We showed that 3,3-dimethylaminopropane-1-hydroxy-1,1-diphosphonic acid (olpadronate) was the most effective bisphosphonate treatment in reducing tumor burden as assessed by GFP imaging and radiography. The GFP tumor area and X-ray score significantly correlated. Reduced tumor growth in the bone was accompanied by reduced serum calcium, parathyroid hormone-related protein, and osteoprotegerin. CONCLUSIONS: The serum calcium, parathyroid hormone-related protein, and osteoprotegerin levels were significantly correlated with GFP area and X-ray scores. Treatment with olpadronate reduced tumor growth in the bone measured by GFP and X-ray imaging procedures. Imaging of GFP expression enables monitoring of tumor growth in the bone and the GFP results complement the X-ray assessment of bone disease. The data in this report suggest that olpadronate has potential as an effective inhibitor of the skeletal progression of clinical prostate cancer.

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. After concentration and electrophoresis, protein bands were excised and subjected to mass spectroscopy analyses. Proteins identified included those associated with protection from oxidative stress, DNA repair, protection from apoptosis, and proteins involved in membrane trafficking and cytoskeletal rearrangement. These novel protein-protein interactions further support the hypothesis that the carboxy-terminus of PTHrP plays a role in cell survival.

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. EXPERIMENTAL DESIGN: PTHrP expression was assessed in paraffin-embedded tumor samples from 407 patients with NSCLC by immunohistochemistry. A pathologist unaware of the clinical history classified specimens as PTHrP positive or PTHrP negative. The log-rank test was used to compare survivals of PTHrP-positive and PTHrP-negative groups, and Cox regression was used to adjust for additional covariates. RESULTS: Median survival was 55 versus 22 months (P < 0.001) in female patients with and without tumor PTHrP, respectively. Male survival was 38 months independent of PTHrP status. Stage, histology, age, and smoking history were also associated with increased longevity. PTHrP remained a significant predictor of survival for female patients after controlling for stage, histology, and age. CONCLUSIONS: In this study, PTHrP expression was associated with a survival advantage in female patients. Additional investigations must be done to ascertain whether the result is reproducible and independent of potential confounding covariates. Sex-dependent effects of PTHrP in lung cancer would open new avenues of research into the role of sex in cancer progression.