Background: Progression of solid tumors not only depends on the complex events initiated by oncogenic lesions, but also on cancer cell ability to divert the function of stromal cells, which become supportive of cancer growth and dissemination.

Aims: In the framework of new anti-cancer strategies, our aim is to concurrently co-target neoplastic cells and stromal Cancer-Associated Fibroblasts (CAF).

Methods: Methodologies include peptide synthesis, cell culture migration and invasion assays, in vivo tumor dissemination experiments, organotypic assays with primary stromal CAFs.

Results: This work is focused on the biological and molecular effects of two novel deca-peptides, denoted as PEP1 and PEP2, which were rationally designed starting from previously disclosed anti-migratory peptides derived from human urokinase (uPA). In vivo, the cyclic derivative PEP2 markedly reduces the number and the size of lung metastases, originated from HT1080 fibrosarcoma cells injected in the mouse tail vein, showing a net anti-metastatic activity. In culture, both peptides counteract the migratory and invasive ability of HT1080 and MDA-MB-231 breast carcinoma cells in Boyden chambers and in 3D-organotypic assays. Noticeably, cell exposure to nanomolar concentrations of either peptides, human dermal fibroblasts (TIF) or primary CAF from breast carcinoma patients (intra- or peri-tumoral) exhibit a reduced pro-invasive ability in 3D-organotypic co-cultures, when tested in combination with either HT1080-GFP fibrosarcoma or MDA-MB-231 mammary carcinoma cells. These effects are accompanied by a reduced capacity to remodel collagen matrix and to secrete chemoattractants, together with a decreased α-SMA and increased Caveolin-1 protein levels, both well known CAF markers.

Conclusions: Overall, these data indicate that two novel decapeptides are efficacious co-targeting agents, counteracting tumor cell dissemination and modulating the pro-invasive activity of stromal fibroblasts.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/novel-urokinase-derived-peptides-inhibiting-the-pro-tumoral-activity-of-cancer-associated-fibroblasts/