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Enhanced Expression of SPARC/Osteonectin in the Tumor-associated Stroma of Non-Small Cell Lung Cancer Is Correlated with Markers of Hypoxia/ Acidity and with Poor Prognosis of Patients¹

Departments of Radiotherapy/Oncology and Pathology, Democritus University of Thrace, Alexandroupolis 68100, Greece [M. I. K., A. G., E. S.]; Departments of Surgery and Pharmacology and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390 [R. A. B.]; Cancer Research United Kingdom, Weatherall Institute of Molecular Medicine and the Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom [K. C. G., A. L. H.]; and Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington 98104 [E. H. S.]

Secreted Protein Acidic and Rich in Cystein (SPARC)/osteonectin is a nonstructural matricellular protein involved in cell-matrix interaction during tissue remodeling and embryonic development. Using a novel monoclonal antibody (10-255), we examined immunohistochemically the patterns of SPARC expression in non-small cell lung cancer (NSCLC). High levels of SPARC in normal lung were confined exclusively to the bronchial cartilage. In NSCLC tissues, cancer cells were unreactive in 107 of 113 cases analyzed (95%), whereas substantial production of SPARC by stromal fibroblasts was noted in 42 of 113 cases (37%). Stromal SPARC was linked with tumor necrosis (P = 0.01) and, marginally, with node metastasis (P = 0.07), as well as with high levels of carbonic anhydrase 9 and LDH in cancer cells (P = 0.0001 and P = 0.01, respectively). SPARC was also coincident with enhanced levels of cancer cell differentiated embryo-chondrocyte expressed gene 1, hypoxia inducible factor 2, and thymidine phosphorylase (P = 0.01, P = 0.05, and P = 0.03, respectively). Although endothelial reactivity for SPARC was noted only in small, immature vessels, SPARC production by stroma cells supported a high degree of vascular maturation (indicated by the presence of subendothelial lamina lucida). Survival analysis revealed a significant association of stromal SPARC with poor prognosis (P = 0.006), a finding that was also confirmed in multivariate models. In NSCLC, SPARC is selectively synthesized by the cells of the tumoral stroma. The strong association of this feature with markers of intratumoral hypoxia and acidity indicates an interesting link between cancer cell metabolism and the induction of a supportive stroma that favors cancer cell invasion and migration that lead to an ominous clinical outcome.

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