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Human Adipose-derived Mesenchymal Stem Cells and Melatonin: In vitro and In vivo Therapeutic Potential in Ovarian Cancer

Grant number: 21/02229-1
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): March 01, 2023
Effective date (End): February 28, 2025
Field of knowledge:Biological Sciences - Morphology - Anatomy
Principal Investigator:Luiz Gustavo de Almeida Chuffa
Grantee:Vinicius Augusto Simao
Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Ovarian cancer (OC) is the fifth leading cause of cancer deaths among women and the most lethal gynecological neoplasm due to its late detection, recurrence and metastasis. Evidence suggests that the tumor microenvironment is composed of heterogeneous populations of cells with different levels of malignancy and that tumor development is driven by a subset of specialized cells, characterized by the properties of self-renewal and multipotency, designated as cancerous stem cells (CSC). CSC can originate from mesenchymal stem cells (MSCs), such as those derived from human adipose tissue (ADSC), which are subject to malignant differentiation into CSCs or cancer-associated fibroblasts (CAFs) from factors secreted by cancer cells, mainly through exosomes, which provides a more aggressive and chemoresistant form of OC against conventional therapies. It has long been shown that melatonin, a hormone secreted by the pineal gland, can act as a potential therapy against cancer due to its antioxidant, immunomodulatory, antiangiogenic and pro-apoptotic functions, suppressing the activity of CAFs and CSC. Moreover, the use of conditioned culture medium (CM) and Paclitaxel (PTX)-treated ADSC exosomes has been proved be effective in inhibiting cancer cells in in vitro and in vivo studies. Therefore, the present study aims to evaluate the melatonin potential in neoplastic differentiation of ADSC mediated by ovarian cancer cells (SKOV-3 and CAISMOV24) and the therapeutic use of ADSC treated with melatonin and its derived exosomes in tumor progression. For this purpose, in vitro studies will be conducted using different methodologies that will allow observing the effect of CM from each cell line, accompanied or not by treatments with melatonin and PTX, evaluated in an independent culture system or in an indirect co-culture. Next, OC cells will be seeded in a non-adherent culture system to assess the formation of multicellular spheroid tumors with ADSC treated with melatonin and PTX or their derived CM. Finally, ADSC will be treated with melatonin or PTX, their CM will be obtained and the isolated exosomes will be administered in an in vivo drug-delivery assay using female BALB/c-nude mice induced with SKOV-3 OC cells. The study will investigate cell viability, cytotoxicity, migration, invasion, and apoptosis, in addition to immunostaining and protein quantification of cellular differentiation markers in CSC and CAFs from each cell line. Next, target proteins will be quantified in the CM of cell cultures by multiplex assay. The exosomes will be submitted to transmission electron microscopy for ultrastructural characterization followed by cellular content analyses using mass spectrometry associated with ontological analysis to obtain the proteomic profiles. Based on these analyzes, we intend to qualify the therapeutic properties of melatonin on ovarian cancer cells and their adjuvant capacity with ADSC to elucidate the understanding about the role of ADSC either promoting inhibition or progression of ovarian carcinoma. In the end, the study hopes to establish a drug-delivery treatment strategy with the association of ADSC and melatonin that is expected to be useful in inhibiting tumor development.

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