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Fibroblast activation protein-?, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations.

ABSTRACT: Cancer associated fibroblasts (CAFs) constitute an abundant stromal component of most solid tumors. Fibroblast activation protein (FAP) ? is a cell surface protease that is expressed by CAFs. We corroborate this expression profile by immunohistochemical analysis of colorectal cancer specimens. To better understand the tumor-contextual role of FAP?, we investigate how FAP? shapes functional and proteomic features of CAFs using loss- and gain-of function cellular model systems. FAP? activity has a strong impact on the secreted CAF proteome ("secretome"), including reduced levels of anti-angiogenic factors, elevated levels of transforming growth factor (TGF) ?, and an impact on matrix processing enzymes. Functionally, FAP? mildly induces sprout formation by human umbilical vein endothelial cells. Moreover, loss of FAP? leads to a more epithelial cellular phenotype and this effect was rescued by exogenous application of TGF?. In collagen contraction assays, FAP? induced a more contractile cellular phenotype. To characterize the proteolytic profile of FAP?, we investigated its specificity with proteome-derived peptide libraries and corroborated its preference for cleavage carboxy-terminal to proline residues. By "terminal amine labeling of substrates" (TAILS) we explored FAP?-dependent cleavage events. Although FAP? acts predominantly as an amino-dipeptidase, putative FAP? cleavage sites in collagens are present throughout the entire protein length. In contrast, putative FAP? cleavage sites in non-collagenous proteins cluster at the amino-terminus. The degradomic study highlights cell-contextual proteolysis by FAP? with distinct positional profiles. Generally, our findings link FAP? to key aspects of CAF biology and attribute an important role in tumor-stroma interaction to FAP?.

SUBMITTER: Koczorowska MM

PROVIDER: S-EPMC5528924 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations.

Koczorowska M M MM Tholen S S Bucher F F Lutz L L Kizhakkedathu J N JN De Wever O O Wellner U F UF Biniossek M L ML Stahl A A Lassmann S S Schilling O O

Molecular oncology 20150811 1

Cancer associated fibroblasts (CAFs) constitute an abundant stromal component of most solid tumors. Fibroblast activation protein (FAP) α is a cell surface protease that is expressed by CAFs. We corroborate this expression profile by immunohistochemical analysis of colorectal cancer specimens. To better understand the tumor-contextual role of FAPα, we investigate how FAPα shapes functional and proteomic features of CAFs using loss- and gain-of function cellular model systems. FAPα activity has a ...[more]

PMID: 26304112

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Project description:The human fibroblast activation protein alpha (FAP alpha) is a M(r) 95,000 cell surface antigen selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. Normal adult tissues are generally FAP alpha-, but some fetal mesenchymal tissues transiently express the molecule. Because of its restricted normal tissue distribution and abundant expression in the stroma of over 90% of breast, colorectal, and lung carcinomas, FAP alpha is under clinical evaluation as a target for immunodetection and immunotherapy of epithelial cancers. In the present study, we have isolated a full-length cDNA for FAP alpha through expression cloning in COS-1 cells. The FAP alpha cDNA codes for a type II integral membrane protein with a large extracellular domain, transmembrane segment, and short cytoplasmic tail. FAP alpha shows 48% amino acid sequence identity to the T-cell activation antigen CD26, a membrane-bound protein with dipeptidyl peptidase IV (DPPIV) activity; however, unlike FAP alpha, CD26 is widely expressed in normal tissues. Three catalytic domains shared by DPPIV homologues in different species and by other serine proteases are conserved in FAP alpha. Immunochemical analysis of COS-1 cells coexpressing FAP alpha and CD26 revealed that the two molecules form heteromeric cell surface complexes, suggesting that a previously identified FAP alpha-associated M(r) 105,000 protein of cultured fibroblasts and growth factor-stimulated melanocytes, FAP beta, is identical to CD26. In vivo coexpression of FAP alpha and CD26 is found in reactive fibroblasts of healing wounds but not in tumor stromal fibroblasts or sarcomas (FAP alpha +/CD26-). The putative serine protease activity of FAP alpha and its in vivo induction pattern may indicate a role for this molecule in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis.

Dataset Information

Fibroblast activation protein-?, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations.

Publications

Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations.

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