Sex-Specific Survival Advantage with Parathyroid Hormone–Related Protein in Non–Small Cell Lung Carcinoma Patients

Abstract

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.Parathyroid hormone-related protein (PTHrP) was discovered as the factor responsible for hypercalcemia of malignancy. As the name implies, PTHrP shares structural similarities with PTH, specifically in the NH 2 -terminal 34 amino acids. Consequently, PTHrP 1-34 binds to the same receptor as PTH 1-34, the type 1 PTH/PTHrP receptor (PTH1R), and duplicates the effects of PTH 1-34 in tissues that bear the receptor, including causing hypercalcemia. Hypercalcemic effects are mediated through decreases in calcium excretion in kidney and increases in calcium release from bone. It is less widely appreciated that PTHrP also exerts effects direct effects on cancer cells that could be important in the pathology of malignancy.

Cytoplasmic and nuclear parathyroid hormone-related proteins are opposing prognostic factors in patients with non-small-cell lung cancer who have undergone curative resection

“…Nuclear H-scores of tumors were significantly lower than their cytoplasmic H-scores (P < 0.001). Hence, based on a review of previous studies of PTHrP in lung cancer (12)(13)(14), a cytoplasmic H-score of 30 or more and a nuclear H-score of 10 or more were considered to represent high PTHrP expression.…”

“…In addition, PTHrP expression has also been reported in variant malignancies and detected in either the cytoplasm or the nucleus (11). However, the prognostic role of PTHrP in lung cancer is still controversial and the results have been conflicting (12)(13)(14). Therefore, we conducted this study to validate whether cytoplasmic or nuclear PTHrP expression is associated with prognosis in patients with NSCLC who have undergone surgical therapy.…”

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

“…Some 66-75% of human NSCLC are PTHrP-positive. 9 PTHrP promoter usage might also be considered, since the thiourea compounds appear to act by inhibiting P3-mediated PTHrP transcription. Thus, a carcinoma with minimal P3 use might not respond well to the compounds.…”

“…PTHrP increases the likelihood of bone metastases in mice injected with small cell lung carcinoma cells 7 and it protects squamous lung carcinoma cells from apoptosis. 8 Since PTHrP is expressed in two-thirds or more of non-small cell lung carcinomas in humans, 9 it could be a reasonable target for a lung cancer therapy.…”

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

“…(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. (27,28) Skeleton devastation due to hyperactive osteoclastogenesis is a hallmark of multiple myeloma (MM), and PTHrP has been postulated to concur to myeloma bone disease because it induces the formation of osteolytic lesions.…”