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Breast tumor cell invasion and pro-invasive activity of cancer-associated fibroblasts co-targeted by novel urokinase-derived decapeptides

Journal Article


Abstract


  • Among peritumoral cells, cancer-associated fibroblasts (CAFs) are major facilitators of tumor progression. This study describes the effects of two urokinase-derived, novel decapeptides, denoted as Pep 1 and its cyclic derivative Pep 2. In a mouse model of tumor dissemination, using HT1080 fibrosarcoma cells, Pep 2 reduced the number and size of lung metastases. Specific binding of fluoresceinated Pep 2 to HT1080 and telomerase immortalised fibroblasts (TIF) cell surfaces was enhanced by ��v overexpression or abolished by excess vitronectin, anti-��v antibodies or silencing of ITGAV ��v gene, identifying ��v-integrin as the Pep 2 molecular target. In 3D-organotypic assays, peptide-exposed TIFs and primary CAFs from breast carcinoma patients both exhibited a markedly reduced pro-invasive ability of either HT1080 fibrosarcoma or MDA-MB-231 mammary carcinoma cells, respectively. Furthermore, TIFs, either exposed to Pep 2, or silenced for ��v integrin, were impaired in their ability to chemoattract cancer cells and to contract collagen matrices, exhibiting reduced ��-smooth muscle actin (��-SMA) levels. Finally, peptide exposure of ��v-expressing primary CAFs led to the downregulation of ��-SMA protein and to a dramatic reduction of their pro-invasive capability. In conclusion, the ability of the novel decapeptides to interfere with tumor cell invasion directly and through the down-modulation of CAF phenotype suggests their use as lead compounds for co-targeting anti-cancer strategies.

Publication Date


  • 2020

Citation


  • Belli, S., Franco, P., Iommelli, F., De Vincenzo, A., Brancaccio, D., Telesca, M., . . . Stoppelli, M. P. (2020). Breast tumor cell invasion and pro-invasive activity of cancer-associated fibroblasts co-targeted by novel urokinase-derived decapeptides. Cancers, 12(9), 1-24. doi:10.3390/cancers12092404

Scopus Eid


  • 2-s2.0-85090172748

Start Page


  • 1

End Page


  • 24

Volume


  • 12

Issue


  • 9

Place Of Publication


Abstract


  • Among peritumoral cells, cancer-associated fibroblasts (CAFs) are major facilitators of tumor progression. This study describes the effects of two urokinase-derived, novel decapeptides, denoted as Pep 1 and its cyclic derivative Pep 2. In a mouse model of tumor dissemination, using HT1080 fibrosarcoma cells, Pep 2 reduced the number and size of lung metastases. Specific binding of fluoresceinated Pep 2 to HT1080 and telomerase immortalised fibroblasts (TIF) cell surfaces was enhanced by ��v overexpression or abolished by excess vitronectin, anti-��v antibodies or silencing of ITGAV ��v gene, identifying ��v-integrin as the Pep 2 molecular target. In 3D-organotypic assays, peptide-exposed TIFs and primary CAFs from breast carcinoma patients both exhibited a markedly reduced pro-invasive ability of either HT1080 fibrosarcoma or MDA-MB-231 mammary carcinoma cells, respectively. Furthermore, TIFs, either exposed to Pep 2, or silenced for ��v integrin, were impaired in their ability to chemoattract cancer cells and to contract collagen matrices, exhibiting reduced ��-smooth muscle actin (��-SMA) levels. Finally, peptide exposure of ��v-expressing primary CAFs led to the downregulation of ��-SMA protein and to a dramatic reduction of their pro-invasive capability. In conclusion, the ability of the novel decapeptides to interfere with tumor cell invasion directly and through the down-modulation of CAF phenotype suggests their use as lead compounds for co-targeting anti-cancer strategies.

Publication Date


  • 2020

Citation


  • Belli, S., Franco, P., Iommelli, F., De Vincenzo, A., Brancaccio, D., Telesca, M., . . . Stoppelli, M. P. (2020). Breast tumor cell invasion and pro-invasive activity of cancer-associated fibroblasts co-targeted by novel urokinase-derived decapeptides. Cancers, 12(9), 1-24. doi:10.3390/cancers12092404

Scopus Eid


  • 2-s2.0-85090172748

Start Page


  • 1

End Page


  • 24

Volume


  • 12

Issue


  • 9

Place Of Publication