De Marzo Laboratory

in the Johns Hopkins Department of Pathology

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Research

Proliferative Inflammatory Atrophy in Prostate Carcinogenesis

Our laboratory focuses on the study of prostate cancer, paying special attention to disease etiology and prevention. We have postulated that inflammation and dietary practices result in injury to prostate epithelial cells (See Figure). This injury results in DNA damage, cell death, regeneration, CpG island gene methylation, mutation and ultimately the formation of prostatic intraepithelial neoplasia (PIN), a neoplastic lesion that can lead to invasive prostate cancer. During this process of injury and regeneration, we have proposed that a common lesion, that is often associated with inflammation arises that we have termed "proliferative inflammatory atrophy" (PIA), and that PIA may represent an intermediate step between normal tissue and PIN and may, therefore, serve as a risk factor lesion for prostate cancer.


New Model (Nat Rev Cancer. 2007;7:256-269 -- See publications page for full details) a figure showing cCellular and molecular model of early prostate neoplasia progression

Cellular and molecular model of early prostate neoplasia progression. a | This stage is characterized by the infiltration of lymphocytes, macrophages and neutrophils (caused either by repeated infections, dietary factors and/or by the onset of autoimmunity); phagocytes release reactive oxygen and nitrogen species causing DNA damage, cell injury and cell death, which trigger the onset of epithelial cell regeneration. The morphological manifestation of the cellular injury is focal prostate atrophy, which is proposed to signify the "field effect" in the prostate. The downregulation of p27, NKX3.1 and phosphatase and tensin homologue (PTEN) proteins in luminal cells stimulates cell-cycle progression. Stress-response genes are induced (such as glutathione S-transferase P1 (GSTP1), GSTA1 and cyclooxygenase 2 (PTGS2)). b | The subsequent silencing of GSTP1 through promoter methylation in subsets of cells further facilitates oxidant-mediated telomere shortening. c | Cells carrying methylated GSTP1 alleles and short telomeres have dysfunctional telomeres and are more likely to bypass the senescence checkpoints. This favours the onset of genetic instability and the consequent accumulation of genetic changes (for example loss of heterozygosity on 8p21,6q or gain of function on 8q24,17q). d | The continued proliferation of genetically unstable luminal cells and the further accumulation of genomic changes, such as gene rearrangements leading to TMPRSS2-ETS family member gene fusions, lead to progression towards invasive carcinomas. PIN, prostatic intraepithelial neoplasia.

These studies have implications for prevention and chemoprevention of prostate cancer--if inflammation is stimulating prostate cancer development, then agents that inhibit the inflammatory response may decrease prostate cancer risk. Also, the elucidation of which agents incite prostate inflammation may lead to eradication of these agents and prevention of cancer.

The MYC Oncogene and Stem Cell Biology in Prostate Cancer Formation

Using human tissue specimens, genetically engineered mouse models, and cell culture systems, our group is studying the role of the MYC oncogene, and a number of its downstream target genes, in prostate cancer cell neoplastic transformation and cell growth regulation. Since MYC is a key regulator of stem cells, these studies have direct implications for stem cell models of prostate cancer formation.

Telomere Shortening in Prostate Carcinogenesis

Many types of cancer, including prostate cancer, show chromosomal instability reflected by aberrations in both number and structure of chromosomes. One route to chromosomal instability is through defective telomeres. Telomeres protect chromosome ends from fusing with other chromosome ends or other chromosomes containing double strand breaks. In conjunction with Alan K. Meeker PhD we have developed a quantitative technique to measure telomere lengths directly in archival tissues and reported that high grade prostatic intraepithelial neoplasia (PIN), the presumed precursor to most prostate cancers, contains abnormally short telomeres, similar to that found in invasive prostatic adenocarcinoma. Similar telomere shortening was found in multiple other organ systems including: breast, colon, head and neck, esophagus, cervix, bladder, and gall bladder. These studies have implications for cancer pathogenesis, as well as for early diagnosis and for monitoring of cancer prevention clinical trials.

Techniques

We employ both human tissues and a number of animal models including genetically engineered mouse and rat models. Some of our methods include immunohistochemistry, immunofluorescence, in situ hybridization, quantitative RT-PCR, methylation specific PCR, bisulfite DNA sequencing, and genome wide gene expression analyzes. The latter molecular methods are often performed after Laser Capture Microdissection of specific cell populations.