The majority of primary cutaneous melanomas go through a prolonged period of dormant growth before acquiring malignant properties. Unlike most other primary tumors, however, this dormancy stage is visible in melanomas, subdermal/orthotopic injection of human melanoma cell lines, obtained from different stages of disease progression, into nude mice. Thus, whereas almost all advanced stage primary or metastatic-derived cell lines give rise to progressively small slow-growing, plaque-like lesions -- similar to radial growth phase (RGP) or thin vertical growth phase (VGP) tumors in humans. Using various methods, e.g. retroviral insertional mutagenesis or gene transfection, this applicant has recently succeeded in isolating tumorigenic variants from a number of such early-stage primary melanomas. These cell lines present an outstanding opportunity to study the basis of pre-malignant melanoma dormancy and the reasons for its termination. First, (based on their recent results), they believe there are three major interconnected factors which govern primary melanoma dormancy. These are: (i) sensitivity to inhibitory controls mediated by several cytokines, including IL-6; (ii) a deficient capacity of melanoma cells to survive in a multicellular growth context; (iii) a deficient ability to induce angiogenesis; Second, overcoming these 'defects' results in acquisition of overt malignant growth characteristics. Third, genetic alterations thought to be involved in the progression of melanomas, such as loss of p21WAF1 or p16INK4, do so by affecting several, or all three phenotypes simultaneously (i.e., cell proliferation, survival, and angiogenesis). Examination of these hypotheses comprise the three specific aims of the research program. The proposed research will shed new light on what is probably the most crucial stage of melanoma progression, but which, thus far, has received little experimental scrutiny because of the lack of appropriate experimental models. It may also serve as a model for factors influencing premalignant-primary tumor dormancy in other types of cancer where access to early-stage lesional material is severely limited, or non-existent.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041233-14
Application #
2856260
Study Section
Pathology B Study Section (PTHB)
Program Officer
Song, Min-Kyung H
Project Start
1992-06-01
Project End
2002-12-31
Budget Start
1999-09-17
Budget End
1999-12-31
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Sunnybrook & Women's Coll Health Sciences Center
Department
Type
DUNS #
City
Toronto
State
ON
Country
Canada
Zip Code
M4 3-M5
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