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SERPINE1 expression discriminates site-specific metastasis in human melanoma.

ABSTRACT: Depth of invasion, a quantifier of vertical growth, is a major cutaneous melanoma staging factor. Stromal penetrance requires pericellular proteolysis regulated by the serine protease and matrix metalloproteinase cascades. The serine protease inhibitor SERPINE1, a poor prognosis biomarker in various cancers, promotes tumor progression likely by titrating the extent and local of plasmin-initiated matrix remodelling. SERPINE1 in human melanoma was assessed using tissue arrays that included primary/metastatic tumors and normal skin. SERPINE1 was basal layer-restricted in the normal epidermis. SERPINE1 immunoreactivity was evident in 27/28 primary (96%) and 24/26 metastatic tumors (92%); cutaneous metastases (80%) had significantly elevated SERPINE1 levels compared with low signals characteristic of lymph node lesions. Moderate SERPINE1 expression was a general finding in primary melanoma, whereas reduced or increased SERPINE1 immunolocalization typified metastatic deposits. The amplitude of SERPINE1 expression may impact melanoma site-specific dissemination, with cutaneous metastases representing a high-SERPINE1 tumor subtype.

SUBMITTER: Klein RM

PROVIDER: S-EPMC3383094 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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SERPINE1 expression discriminates site-specific metastasis in human melanoma.

Klein R Matthew RM Bernstein Daniel D Higgins Steven P SP Higgins Craig E CE Higgins Paul J PJ

Experimental dermatology 20120701 7

Depth of invasion, a quantifier of vertical growth, is a major cutaneous melanoma staging factor. Stromal penetrance requires pericellular proteolysis regulated by the serine protease and matrix metalloproteinase cascades. The serine protease inhibitor SERPINE1, a poor prognosis biomarker in various cancers, promotes tumor progression likely by titrating the extent and local of plasmin-initiated matrix remodelling. SERPINE1 in human melanoma was assessed using tissue arrays that included primary ...[more]

PMID: 22716255

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Project description:Adoptive immunotherapy using ex vivo expanded tumor reactive lymphocytes can mediate durable cancer regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their anti-tumor efficacy. Thus, there is significant clinical interest in the prospective isolation of tumor specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8+ T cells (TCM) have divergent capabilities including effector differentiation to target antigen and stem cell-like self renewal that enable long term survival after adoptive transfer. In this study, we sought to isolate human melanoma specific TCM to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high throughput identification of these rare cells from patients, we report that TCM have a defined stoichiometric production of IL-2 and IFN-g mRNA after antigen stimulation. Melanoma specific T cells screened for high relative IL-2 production possessed a TCM phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self renewal capability, melanoma specific TCM underwent in vitro expansion and differentiation into lytic effector clones and then were adoptively transferred back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental TCM attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human TCM-derived clones, but further efforts to improve their anti-tumor efficacy are still necessary. We used microarrays to compare the resting gene expression profile of melanoma specific CD8+ T cell clones that were derived from either High IL-2:IFN index precursors or Low IL-2:IFN index precursors. Three melanoma specific effector clones were derived from parental cells that possessed a high IL-2:IFN index from three independent patients with metastatic melanoma. Two melanoma specific effector clones were derived from parental cells that possessed a low IL-2:IFN index from two independent patients with metastatic melanoma. We used microarrays to compare the resting gene expression profile of the CD8+ T cell clones that were derived from either high IL-2:IFN index precursors or low IL-2:IFN index precursors.

Dataset Information

SERPINE1 expression discriminates site-specific metastasis in human melanoma.

Publications

SERPINE1 expression discriminates site-specific metastasis in human melanoma.

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