Targeting ‘Normal’ Cells to Treat Cancer

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Crystal structure of human FAP - pdb ID=1z68

Crystal structure of human FAP - pdb ID=1z68

Most cancer treatments directly target the cancerous cells but tumours are a heterogeneous mix of transformed cells and ‘normal’ cells. Stromal cells, including infiltrating inflammatory and immune cells, endothelial cells, pericytes, and tumour-associated fibroblasts (TAFs), play a key role in cancer growth and progression, both directly though cell contact and indirectly through paracrine/exocrine signalling, protease activity and modulation of the extracellular matrix. Identifying stromal targets could provide a complementary strategy to directly targeting cancer cells but the widespread expression of many proteases limits their potential for therapeutic intervention.

A team of scientists led by researchers at the Wistar Institute has now identified a critical role for fibroblast activation protein (FAP), expressed by TAFs, in promoting tumour growth in mice. FAP is a type II cell surface serine protease expressed predominantly by fibroblastic cells in areas of active tissue remodelling such as tumour stroma, fibrosis, or healing wounds. FAP is a member of the post-proline dipeptidyl aminopeptidase family, sharing the highest similarity with dipeptidyl peptidase IV (DPPIV) but, unlike DPPIV, FAP is not found in benign lesions or normal adult tissues.

PT630 structure

PT630

The team found that the enzymatic activity of endogenous FAP promoted tumour growth in mouse models of lung and colon cancer and, moreover, that genetic deletion of FAP expression, or pharmacological inhibition of FAP activity using PT630, was able to significantly inhibit tumour cell proliferation. Inhibition of FAP activity was further shown to disrupt the organisation of collagen fibres in the extracellular matrix and decrease blood vessel density in tumours.

FAP is expressed in 90% of solid tumours and the study, which is published in the Journal of Clinical Investigation, suggests that therapies that target stromal cells could increase the effectiveness of cancer cell-targeted therapies for solid tumours.


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