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 2alpha, 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.