Estudos in vivo da atividade antitumoral de uma desintegrina inibidora da integrina αvβ3

Abstract

Cancer represents a complex ecosystem composed of tumor cells and a diverse population of non-malignant cells embedded within an altered extracellular matrix. The tumor microenvironment (TME) comprises various immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and several additional tissue-resident cell populations. These host cells were once regarded as mere bystanders in tumorigenesis but are now recognized as playing critical roles in cancer pathogenesis. During vascular remodeling and angiogenesis, for example, endothelial cells upregulate the expression of several cell-surface molecules that promote tumor cell invasion and proliferation, including integrin αvβ3. Integrin αvβ3 is a vitronectin receptor that recognizes the adhesive motif RGD and plays an essential role in directing cell migration. Our group has previously investigated this integrin using the recombinant disintegrin DisBa-01, derived from Bothrops alternatus venom and produced as a His-tag recombinant protein through heterologous expression and purification. The aim of the present study was to evaluate the potential effects of the pharmacological inhibition of integrin αvβ3 on angiogenesis and tumor progression in a syngeneic experimental model of triple-negative breast cancer. The effects of local and systemic inhibition of integrin αvβ3 on primary tumor development were evaluated in female BALB/c mice inoculated with 4T1Br4-mCherry cells. Following tumor establishment, the animals were allocated into two experimental models (Non-surgical Spontaneous Metastasis and Surgical Spontaneous Metastasis), each comprising three groups (Control Group 1, DisBa-01 Group, and Control Group 2), and were treated for a defined period. After euthanasia, tissue samples from multiple organs were collected for subsequent real-time quantitative PCR, histological, and immunofluorescence analyses. The study was approved by the Animal Ethics Committee of the Federal University of São Carlos under protocol number 9550180823. The results demonstrated that pharmacological inhibition of integrin αvβ3 by DisBa-01 modulated the tumor microenvironment, producing both pro-tumorigenic and antitumor effects in both experimental models. Increased collagen deposition was observed in tumors from Experiment 1, whereas a greater potential for tumor recurrence was detected in the DisBa-01-treated group in Experiment 2. In addition, reduced pulmonary metastasis was confirmed by qPCR in both experiments. Comparatively, animals that did not undergo surgery exhibited a better therapeutic response, whereas the surgical model showed greater metastatic dissemination and reduced survival. Collectively, these findings indicate that inhibition of integrin αvβ3 alone was insufficient to restrain tumor progression in vivo, highlighting the need for further studies to elucidate its relationship with the tumor microenvironment.