Function of Periecan Domain 1 in Prostate Cancer
Abstract
Preferential metastasis of prostate cancer (PCa) to bone marrow contributes to disease mortality and morbidity. Local factors present in the bone stromal extracellular matrix (ECM) increase metastatic tumor growth through paracrine interactions among tumor, stromal and endothelial cells present in the microenvironment. Heparin binding growth factors (HBGF) present in bone marrow provide growth and survival signals to metastatic PCa cells. Perlecan (Pln), the major heparan sulfate proteoglycan (HSPG) in the bone marrow stromal ECM functions as a co-receptor to deliver HBGFs to high affinity receptors. HSchains on Pln are located in a unique N-terminal domain I (PlnDI) which serves as a co-receptor for HBGFs. We hypothesized that Pln, specifically PlnDI, delivers HBGFs to the PCa cell surface, promotes cell survival and protects from apoptosis. We used three PCa cell lines: LNCaP, C4-2B, and PC3 to study the function of PlnDI. We harvested conditioned medium (CM) from bone stromal cell lines, HS27a and HS5, which produce abundant Pln. The proteoglycan rich fraction containing Pln was obtained using anion exchange bead chromatography, then tested as a survival factor for the three different PCacell lines. DNA fragmentation experiments showed that bone stromal derived Pln from CM protected all three lines of PCa cells from camptothecin induced apoptosis. We also supplied purified, fully glycosylated recombinant PlnDI protein to PCa cells, which also protected cells from apoptosis. Pln knockdown clones grow poorly compared to the parental or control transfected C4-2B cells (Ref.1).Interestingly, knockdown cells weremore susceptible to apoptosis in response to the apoptosis inducers anti-Fas and camptothecin, and exogenous PlnDI rescued survival. We followed this up by undertaking to identify natural factor(s) produced by bone marrow stromal cells that induces apoptosis in PCa cells. We found that this apoptosis inducing activity is specific for LNCaP derived lines.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2006
- Accession Number
- ADA462907
Entities
People
- Chu Zhang
- Mary C. Farach-carson
Organizations
- University of Delaware