Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer

Biomedicines

卷:9

Carlo Cota¹  Emilia Migliano²  Barbara Bellei³  Gianluca Lopez³  Mauro Picardo³  Silvia Caputo³  Valeria Marcaccini³ 

[1] Department of Dermatology, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;

[2] Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;

[3] Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, 00144 Rome, Italy;

关键词: CAFs;    skin cancer;    tumor stroma;    inflammation;    microenvironment;   

DOI  :  10.3390/biomedicines9060597

来源: DOAJ

【 摘 要 】

Background: Cancer-associated fibroblasts (CAFs) facilitate many aspects of cancer development by providing a structural framework rich in bioactive compounds. There are emerging studies proposing a combination of conventional anti-cancer therapies directed against neoplastic cells to molecules targeting tumor microenvironments. Methods: The study evaluated the pharmacological properties of the anti-tumor agent paclitaxel conjugated to hyaluronic acid (HA) regarding non-melanoma skin cancer (NMSC) and the surrounding fibroblasts. This molecule, named Oncofid-P20 (Onco-P20), preferentially targets cells expressing high levels of CD44, the natural ligand of HA. Results: Consistent with paclitaxel’s mechanism of action involving interference with the breakdown of microtubules during cell division, highly sensitive carcinoma cells rapidly underwent apoptotic cell death. Interestingly, less sensitive cells, such as dermal fibroblasts, resisted the Onco-P20 treatment and experienced a prolonged growth arrest characterized by morphological change and significant modification of the gene expression profile. Onco-P20-treated fibroblasts exhibited reduced growth factor production, downmodulation of the Wnt signaling pathway, and the acquisition of a marked pro-inflammatory profile. Independently of direct exposure to taxol, in the presence of Onco-P20-treated fibroblasts or in their conditioned medium, carcinoma cells had a reduced proliferation rate. Similar to NHF, fibroblasts isolated from skin cancer lesions or from adjacent tissue acquired anti-neoplastic activity under Onco-P20 treatment. Conclusion: Collectively, our data demonstrate that Onco-P20, exerting both a direct and an NHF-mediated indirect effect on carcinoma cells, is a candidate for an innovative therapy alternative to surgery for the treatment of NMSC.

【 授权许可】

Unknown