Abstract
Cartilage is resistant to tumor invasion. In the present study, we found that the NH(2)-propeptide of the cartilage-characteristic collagen, type IIB, PIIBNP, is capable of killing tumor cells. The NH(2)-propeptide is liberated into the extracellular matrix prior to deposition of the collagen fibrils. This peptide adheres to and kills cells from chondrosarcoma and cervical and breast cancer cell lines via the integrins alpha(v)beta(5) and alpha(v)beta(3). Adhesion is abrogated by blocking with anti alpha(v)beta(5) and alpha(v)beta(3) antibodies. When alpha(v) is suppressed by small intefering RNA, adhesion and cell killing are blocked. Normal chondrocytes from developing cartilage do not express alpha(v)beta(3) and alpha(v)beta(5) integrins and are thus protected from cell death. Morphological, DNA, and biochemical evidence indicates that the cell death is not by apoptosis but probably by necrosis. In an assay for invasion, PIIBNP reduced the number of cells crossing the membrane. In vivo, in a tumor model for breast cancer, PIIBNP was consistently able to reduce the size of the tumor.
Highlights
From the ‡Department of Orthopedic Surgery and §Department of Cell Biology and Physiology, Washington University School of Medicine, Barnes-Jewish Hospital, St
PIIBNP Adheres to Cells via Integrins—Type II procollagen is unique among the fibrillar collagens in containing vicinal RGD peptides in the NH2-propeptide domain (Fig. 1A)
Type IIB collagen is the predominant collagen in hyaline cartilage and the endochondral bone growth plate, comprising 50% of the protein within the ECM
Summary
Type IIA procollagen is not processed to remove the NH2-propeptide, and the entire pN-procollagen is deposited into the ECM It functions to bind growth factors like BMP-2 and transforming growth factor- via the von Willebrand factor C domain encoded by exon 2 [14]. Type IIB Collagen NH2-propeptide Kills Tumor Cells them at low levels, we propose that during development, chondrocytes are resistant to the influence of the type IIB collagen NH2-propeptide that they synthesize Because these data suggest that PIIBNP might be a useful therapeutic agent for cancer, we tested the anti-invasive property of PIIBNP and established a breast cancer model in mice to demonstrate that PIIBNP is able to reduce tumor size in vivo
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