FAP

Official Full Name

fibroblast activation protein alpha

Organism

Homo sapiens

GeneID

2191

Background

The protein encoded by this gene is a homodimeric integral membrane gelatinase belonging to the serine protease family. It is selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. This protein is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

Synonyms

FAPA; SIMP; DPPIV; FAPalpha;

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Detailed Information

Fibroblast activation protein (FAP) is one of the important markers on the surface of tumor-associated fibroblasts. It is highly expressed in more than 90% of epithelial cancer stromal fibroblasts and plays an important role in the occurrence and development of tumors. FAP belongs to the DPP Ⅳ protein family and can specifically hydrolyze the peptide bonds formed by proline and other small molecules after the Gly-Pro sequence.

FAP-α is a serine protease. Researchers first discovered monoclonal antibody F19 in the study of epithelial cancer tumor stromal fibroblasts. F19 can express most soft tissue sarcomas, wound healing granulation tissue and certain fetal mesenchymal components. But it is not expressed in the benign tumor stroma, normal or malignant epithelial cells, malignant hematopoietic tumor cells, fetal kidney, colon and normal lung stromal fibroblasts, cartilage and skeletal muscle. Subsequently, the protein identified by monoclonal antibody F19 was named FAP-α. FAP-α is a member of the S9b peptidase family and is expressed in activated stromal fibroblasts and reconstructed tissues. It is a type II cell surface-bound transmembrane glycoprotein (mr95 000), which can participate in extracellular matrix remodeling. FAP-α is a serine protease involved in extracellular matrix remodeling. It is highly expressed on the surface of more than 90% of malignant epithelial tumor stromal fibroblasts, but it is not detected in normal adult tissues.

Figure 1. Intricate interaction of tumor cells with FAPα in tumor microenvironment. (Zi, F., et al. 2015)

Biological Characteristics of Fap

FAP-α has endonuclease activity for cleaving peptide chains such as gelatin, type I collagen, α2 anti-fibrase, and participates in the degradation of TME, which promotes tumor cells to separate from the original site for further infiltration and metastasis. The enzymatic activity of FAP-α that promotes tumor cell growth is divided into direct and indirect effects. It works in the following four ways: (1) it degrades extracellular matrix, promotes the invasion and metastasis of tumor cells, and participates in the remodeling of tumor tissues; (2) By activating another proteinase, the extracellular matrix is degraded, and then TME is indirectly degraded; (3) Dissociate the growth factors related to TME (including transforming growth factor-β and platelet-derived growth factor, etc.), and promote malignant transformation of tumor cells; (4) In the process of tumor cell growth, it participates in the formation of tumor microvessels. FAP-α can activate stored transforming growth factor-β and vascular endothelial growth factor in the matrix. It activates transforming growth factor-β in TME by proteolyzing the transforming growth factor binding protein rich in proline and protease-sensitive hinge regions, leading to an increase in FAP-α expression.

FAP-α can be expressed not only in tumor stromal fibroblasts, but also in tumor cells of certain tumor tissues. Therefore, targeted therapy with FAP-α surrounding the target can not only act on fibroblasts of tumor stroma, but also inhibit the stroma on which tumor cells depend for survival. It can also act on tumor cells and directly kill tumor cells.

Fap and Tumor Treatment

Studies have shown that under hypoxic conditions, cancer-associated fibroblasts in breast cancer tissues can participate in regulating the expression of vascular endothelial growth factor in tumors by up-regulating the hypoxia-inducible factor-1α/G protein-coupled estrogen receptor signaling pathway, which in turn promotes the proliferation of human umbilical vein endothelial cells and ultimately leads to the formation of new capillaries in tumor tissues. In vivo studies have shown that the increase in FAP-α expression is related to the increase in tumor growth rate and can promote the formation of new blood vessels. The above research results show that FAP-α plays an important role in promoting tumor microvessel formation. Cytotoxic drugs targeting FAP-α can selectively accumulate around the tumor's new microvessels and provide favorable regulation for effectively blocking the blood supply of tumors. This may become an effective and potential new target for tumor treatment.

References:

Zi, F. , He, J. , He, D. , Li, Y. , Yang, L. , & Cai, Z. . (2015). Fibroblast activation protein α in tumor microenvironment: recent progression and implications (review). Molecular Medicine Reports.
Pure, Ellen, Blomberg, & Rachel. (2018). Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics. Oncogene.
Jiuyang, Liu, Chaoqun, Huang, Chunwei, & Peng. (2018). Stromal fibroblast activation protein alpha promotes gastric cancer progression via epithelial-mesenchymal transition through wnt/ β-catenin pathway. Bmc Cancer.

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