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

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 targ...

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Autores principales: Bellei, Barbara, Caputo, Silvia, Migliano, Emilia, Lopez, Gianluca, Marcaccini, Valeria, Cota, Carlo, Picardo, Mauro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225214/
https://www.ncbi.nlm.nih.gov/pubmed/34073987
http://dx.doi.org/10.3390/biomedicines9060597
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author Bellei, Barbara
Caputo, Silvia
Migliano, Emilia
Lopez, Gianluca
Marcaccini, Valeria
Cota, Carlo
Picardo, Mauro
author_facet Bellei, Barbara
Caputo, Silvia
Migliano, Emilia
Lopez, Gianluca
Marcaccini, Valeria
Cota, Carlo
Picardo, Mauro
author_sort Bellei, Barbara
collection PubMed
description 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.
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spelling pubmed-82252142021-06-25 Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer Bellei, Barbara Caputo, Silvia Migliano, Emilia Lopez, Gianluca Marcaccini, Valeria Cota, Carlo Picardo, Mauro Biomedicines Article 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. MDPI 2021-05-24 /pmc/articles/PMC8225214/ /pubmed/34073987 http://dx.doi.org/10.3390/biomedicines9060597 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bellei, Barbara
Caputo, Silvia
Migliano, Emilia
Lopez, Gianluca
Marcaccini, Valeria
Cota, Carlo
Picardo, Mauro
Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer
title Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer
title_full Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer
title_fullStr Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer
title_full_unstemmed Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer
title_short Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer
title_sort simultaneous targeting tumor cells and cancer-associated fibroblasts with a paclitaxel–hyaluronan bioconjugate: in vitro evaluation in non-melanoma skin cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225214/
https://www.ncbi.nlm.nih.gov/pubmed/34073987
http://dx.doi.org/10.3390/biomedicines9060597
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