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Evaluation of changes of extracellular matrix and phototherapy in lineages tumor cell

Grant number: 18/09796-6
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2019
Effective date (End): March 31, 2021
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal Investigator:Manoel João Batista Castello Girão
Grantee:Gislaine Patricia de Andrade
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The incidence rates of breast cancer are high in Brazil, despite advances in diagnosis and treatment. Moreover, the high recurrence of breast cancer is directly associated with the spread of tumor cells, which can lead to distant metastases. Some risk factors for breast cancer development are well established, like genetic factors with mutation in genes such as BRCA1 and BRCA2, TP53 and PTEN. Skin cancer is one of the most common cancer types in the world population and one of the most frequent in Brazil, due to the great solar incidence in the country. Melanoma is the most lethal skin cancer and its incidence has increased over the past few decades. Some therapies are being used in melanoma's treatment, such as BRAF-targeted drugs and inhibitory drugs in MEK, but they are likely to cause severe side effects to patients. Photodynamic therapy (PDT) comprises the administration of a photosensitizer that, after accumulation in the affected tissue, is exposed to light of specific wavelength. This process generates reactive oxygen species (ROS), which are capable of triggering cell death by specific reactions. PDT can be used in the treatment of cancer and has shown fewer side effects when compared to other antineoplastic therapies. Hypericin, a third generation photosensitizer, possesses great effectiveness in promoting cell death in tumor cells after photoactivation. The present study's objective is to evaluate the photodynamic effects of hypericin and its derivatives in breast cancer and melanoma using two-dimensional culture (2D), three-dimensional culture (3D) and animal model (zebrafish embryos), evaluating the photoactivation effect on cell signaling mechanisms and extracellular matrix. The strategies used in this study include trials for evaluation of the photodynamic effect in viability and clonogenicity of both breast and melanoma tumor cells, as well as its effect in the tumor growth in vivo. Signaling pathways and possible alterations of the extracellular matrix will also be investigated, with the expression of metalloproteases, heparanase and proteoglycans, molecules directly related to carcinogenesis. The results obtained may highlight the potential use of PDT as an alternative treatment for both breast cancer and melanoma, as well as elucidate important molecular mechanisms and extracellular matrix changes for tumor development.