Interaction of Prostate Cancer Cells with Disorganized Bone Matrix Provides Resistance to Radiation-Induced Death In Vitro
Cancer and Bone (Basic, Trans. and Clinical)
Bone, Cartilage and Connective Tissue Matrix & Development (Basic)
Poster Sessions, Presentation Number: SU0119
Session: Poster Session II
Sunday, September 13, 2009 12:00 AM - 12:00 AM, Colorado Convention Center, Exhibit Hall F
* , UNITED STATES, Katie Lowther, University of Connecticut Health Center, Catherine Kessler, University of Connecticut Health Center, Paul Campagnola, University of Connecticut Health Center, , UNITED STATES
The metastasis of prostate cancer to bone frequently results in an “osteoblastic” lesion in which cancer cells induce the degradation of normal bone, and its replacement by an inferior, disorganized bone matrix. It is unclear why prostate cancer cells induce such a reaction. The purpose of this study was to determine whether interaction of metastatic prostate cancer cells with organized vs. disorganized bone matrix would differentially affect gene expression and resistance to radiation-induced cell death.
Wild type mouse osteoblast cultures were used to synthesize a mineral rich, well organized bone matrix. Osteonectin/SPARC regulates collagen fibril assembly, therefore osteonectin-null osteoblasts were used to synthesize a hypomineralized bone matrix containing poorly structured collagen fibrils. Second harmonic generation imaging of matrices confirmed differences in collagen fibril organization, whereas Western blot analysis did not demonstrate significant differences in collagen content per microgram of matrix. Following removal of the osteoblasts, matrices were seeded with PC-3 cells (derived from a prostate carcinoma bone metastasis). Actin staining and confocal microscopy showed that PC-3 cells interacting with the organized bone matrix developed a fibroblastic morphology, but cells interacting with the poorly structured matrix retained a more rounded, compact shape. Ingenuity Pathway Analysis of data obtained from Illumina expression arrays suggested that interaction of PC-3 cells with disorganized bone matrix increased expression of genes associated with the ERK signaling pathway, lipid metabolism, and cell survival. Interestingly, LNCaP cells (derived from a prostate carcinoma lymph node metastasis) also showed matrix-mediated changes in gene expression, although they did not display differences in cell morphology when interacting with the matrices. Exposure of PC-3 cells seeded on the organized bone matrix to gamma radiation (4 Gy) resulted in an 80% decrease in cell viability, whereas cells seeded on the disorganized matrix only had a 50% decrease in viability (p<0.01). We hypothesize that interaction of prostate carcinoma cells with disorganized bone matrix, which may result from the “osteoblastic” response triggered by these cells in the skeleton, leads to a gene expression profile that favors resistance to radiotherapy.
* Presenting Authors(s):
, UNITED STATES