Under-Expression of Nuclear Matrix Protein Sp100: A Basis for Why Prostate Cancer Nuclei Look Different Than Benign Nuclei.
Lawrence D True, Ilsa Coleman, David Gifford, Roger Coleman, Peter Nelson. University of Washington, Seattle; Fred Hutchinson Cancer Research Center, Seattle
Background: Nuclear histological features – nucleomegaly, nucleolomegaly, irregular nuclear membranes, and irregular coarse clumping of heterochromatin – distinguish cancer from non-cancer cells in such solid organs as the prostate. However, the molecular basis of these structural features is unknown. DNA aneuploidy is an insufficient explanation; only a minority of prostate cancers is characterized by changes in DNA ploidy. We hypothesized that changes in expression level of nuclear matrix proteins underlie the histologic features of carcinoma nuclei and, thus, might be used as molecular markers of cancer.
Design: Cancer and paired non-carcinoma luminal epithelial cells were laser-microdissected from 35 primary carcinomas of the prostate, Gleason grades 6 through 9. Amplified cDNA was hybridized to oligonucleotide microarrays. Samples from each adjacent tissue block were used to create tissue microarrays of formalin-fixed paraffin embedded tissue. Sections of this TMA and of 3 additional TMAs (50 prostate cancers altogether) were immunostained for nuclear matrix protein SP100 using a commercially available antibody (AbCAM. 1:800). SP100 expression levels were recorded on a 4-point scale (absent, faint/focal, intense in the minority or intense in the majority of cells). The median expression levels of cancer and non-cancer cells from all cases were compared.
Results: Nuclear matrix protein SP100 transcripts were differentially expressed to the greatest degree of all matrix genes, from 0.5 to 2-fold greater in normal luminal cells compared with paired cancer cells from 33 of the 35 same 10 prostates. Degree of expression did not correlate with the grade of the cancer. The median expression values of immunohistochemically defined protein in the TMAs was faint for cancer cells and intense in >75% of benign luminal cells.
Conclusions: We identified a nuclear matrix protein, SP100, which is expressed at lower levels in cancer cell nuclei compared with non-cancer luminal cell nuclei. Since SP100 inhibits expression of ets1, a transcription factor that enhances production of tissue matrix proteases, under-expression of SP100 by cancer cells may facilitate invasion by repressing SP100 mediated inhibition of protease expression. Our finding also begins to provide a molecular basis for the histologic features of cancer cells, which enable pathologists to microscopically distinguish cancer cells from non-cancer cells.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 1:00 PM
Poster Session II # 145, Monday Afternoon