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Tumor Microenvironment Grant: Mechanisms of Tumor Cell Dormancy

Mechanisms of Prostate Cancer Dormancy in the Bone Marrow Niche

PCa Cells in Mouse Marrow Legend: Prostate Cancer is a common neoplasm and the second leading cause of cancer deaths in American males. The high mortality rate is due mainly to the spread of malignant cells to many tissues including bone. This photograph demonstrates molecular mimicry of PCa cells which may facilitate their ability to evade detection. Here, human PCa cells in the marrow of a severe combined immune deficient (SCID) mouse are shown to express the transcription factor Runx2, is normally expressed by marrow osteoblasts. The obliteration of the normal runx2 signal demonstrates that “the monster within” has taken over the marrow.

The image is a differential interference contrast (DIC) microscopy photograph overlaid with PCa cells stained green (using an antibody to human leukocyte antigens (HLA) – A,B,C). Runx-2 is stained with an antibody hooked to a red fluorochrome. Almost no red was observed and only green (PCa) or yellow (Red and green or PCa expressing Runx2) is seen.

PI name: Russell Taichman (rtaich@umich.edu)
Institute: University of Michigan at Ann Arbor
Co-PIs: Kenneth Pienta (kpienta@umich.edu) Yusuke Shiozawa (shiozawa@umich.edu)

Mr. W. is a 66-year-old man. Six years ago he was diagnosed with a moderately differentiated, localized prostate cancer (PCa) when he presented for a routine physical exam and was found to have a prostate specific antigen (PSA) blood test of 5.2. Digital rectal exam revealed no abnormalities but prostate ultrasound and biopsy revealed a Gleason 4+3 = 7 cancer in 2/12 biopsy cores (clinical stage TIcNxMx). Because Mr. W. was in otherwise excellent health, he chose to undergo a radical retropubic prostatectomy and his prostate was removed. All of his lymph nodes were negative for cancer. He was considered to be cured of his disease. One year ago, Mr. W.’s PSA became detectable and he now has three lesions present on bone scan. He has metastatic prostate cancer, now incurable. Each year, approximately 40,000 men who should have been cured of their prostate cancer by surgery or radiation therapy present with incurable metastatic disease that will manifest itself as metastatic lesions in the bone, usually years after primary treatment. The only explanation for this is that disseminated tumor cells (DTCs) are present in the bone microenvironment before surgery or radiation eradicated the primary tumor. Clearly the ability of DTCs to proliferate, undergo apoptosis or become dormant must occur soon after the initial arrest of circulating tumor cells (CTCs) in the marrow. Unquestionably, a greater understanding of the molecular events that regulate a DTC’s ability to become and remain dormant over long periods is crucial to define new therapeutic strategies to combat disease progression. How these cells traffic to the bone, become dormant and then ultimately begin to proliferate is the subject of this TMEN application. The proposed TMEN is composed of highly interactive and complementary projects that are supported by a human sample acquisition core (HSAC). Ultimately this work will lead to defining new therapeutic strategies to combat PCa skeletal metastases. The findings generated by this program will lead to a significant impact on the health and well being of men with PCa. The global hypothesis is that DTCs target the hematopoietic stem cell (HSC) niche during metastasis. Once in the niche, the niche regulates dormancy of DTCs. When DTCs are able to overcome the growth regulatory effects of the HSC niche, metastatic foci develop.

TMEN Collaborative U01s
Tumor Microenvironment Network

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