Nuclear Expression of PTHrP and Outcome in Non-Small Cell Lung CancerRandolph H. Hastings and Leonard J. DeftosVA San Diego Healthcare System
Parathyroid Hormone-related Protein (PTHrP) • Responsible for hypercalcemia of malignancy • Homology with parathyroid hormone 1-34 • Reproduces the actions of PTH • Acts as a local growth factor • Expressed in all types of lung cancer
P PTHrP Isoforms
P PTHrP Processing
Nuclear Localization of PTHrP • Two nuclear localization sequences • NLS have clusters of basic residues
Nuclear PTHrP Exerts Intracrine Effects • Intracrine actions alter growth or apoptosis • Intracrine effects may oppose cell surface effects
TUNEL staining in A549 cells after hydrogen peroxide vector PTHrP 1-87 PTHrP 1-173
Opposing Effects of PTHrP on Apoptosis in Lung Cancer Cells • Paracrine effects protect. • Intracrine effects sensitize.
PTHrP and Cancer • Expressed in many cancers, with and without associated hypercalcemia • Growth factor for many cancer cell lines • Favors bone metastasis in animal models • Associated with improved survival in breast cancer
Hypothesis Nuclear expression of PTHrP and/or expression of PTHrP 1-173 increases survival in patients with non-small cell lung cancer.
Evaluate survival as a function of PTHrP expression • Stain lung cancer sections for PTHrP protein and mRNA for the PTHrP isoforms. • Collect survival, stage, histology, age and gender data from computerized cancer registry • Analyze effect of PTHrP on 12-month survival with a Cox proportional hazards model
Resources • Well established immunohistology laboratory • VA San Diego Cancer Registry (570 NSCLC patients) • UCSD Tumor Registry (1286 NSCLC patients) • UCSD Cancer Center Biostatistics Resource
Opportunities for Collaboration • Pathologist to assist with slide evaluation • Oncologist to discuss clinical relevance, consider future studies