Tackling Metastasis with Gold Nanoparticles: Inhibition of Intercellular Communication Mediated by Cancer Cells-Derived Exosomes

• Autor(a) principal: Carvalho, António
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/133583
• topic: metastasis; organotropism; breast cancer; exosomes; integrins α6β1 and α6β4; gold nanoparticles; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Metastases are accountable for at least 66.7% of cancer deaths, implying a terminal illness for the great majority of patients diagnosed with metastatic cancer. The last and rate-limiting step in invasion-metastasis cascade is colonization. Colonization is the process by which disseminated tumour cells penetrate distant tissues and adapt to the foreign “soil” in order to prosper. To hasten colonization, cancer cells often secrete soluble factors and extracellular vesicles such as exosomes through systemic circulation, which ultimately lead to creation of tumour permissive microenvironments at secondary organs, pre-metastatic niches. Exosomal integrins α6β1 and α6β4 secreted by MDA-MB-231 cells, a human breast cancer cell line, were found to specifically fuse with lung-resident fibroblasts and epithelial cells. The cargo release within recipient cells activates Src and upregulates pro-inflammatory S100 genes, which generates lung pre-metastatic niches and promotes lung tropic metastasis. In this case, cell-cell communication via exosomes between primary tumour cells and microenvironment of distant organs is a key mediator of metastasis progression. Taken into account the recent bet on antisense oligonucleotides therapeutics and the advent of nanotechnology, a gold-nanoconjugate with gene silencing activity was produced. This was achieved by functionalizing gold nanoparticles with an antisense oligonucleotide designed to silence ITGA6, the gene that encodes the α6 subunit, present in integrins α6β1 and α6β4. The silencing efficacy was evaluated using MDA-MB-231 cells at the RNA and protein levels, and the existence of phenotypical changes between untreated and treated cells was assessed. The nanoconjugate showed silencing activity. Reduced cellular levels of integrins α6β1 and α6β4 may lead to diminished packaging of these receptors into exosomes and impairment of integrin-mediated lung tropic metastasis. This nanoscale approach has potential to be employed to prevent lung metastasis, but further studies are required.