Abstract
Distant metastasis is the primary cause of death in the majority of the cancer types. Recently, much importance has been given to tumor microenvironment (TME) in the development of invasive malignant tumors, as well as the metastasis potential. The ability of tumor cells to modulate TME and to escape immune-mediated attack by releasing immunosuppressive cytokines has become a hallmark of breast cancer. Our study shows the effect of IV formulation of HET0016 (HPßCD-HET0016) a selective inhibitor of 20-HETE synthesis, administered intravenously in immune-competent in vivo mouse model of murine breast cancer. 4T1 luciferase positive cells were implanted to the mammary fat pad in Balb/c mice. Treatment started on day 15, and was administered for 5 days a week for 3 weeks. The development of metastasis was detected via optical imaging. Blood, spleen, lungs, bone marrow and tumor were collected for flow cytometry, to investigate changes in myeloid-derived suppressive cells (MDSCs) populations and endothelial phenotype. Tumor and lungs were collected for protein analysis. Our results show that HPßCD-HET0016: (1) decreased tumor volume and lung metastasis compared to the vehicle group; (2) reduced migration and invasion of tumor cells and levels of metalloproteinases in the lungs of animals treated with HPßCD-HET0016 via PI3K/AKT pathway; and (3) decreased expression of pro-inflammatory cytokines, growth factors and granulocytic MDSCs population in the lung microenvironment in treated animals. Thus, HPßCD-HET0016 showed potential in treating lung metastasis in a preclinical mouse model and needs further investigations on TME.
Highlights
A major challenge in treatment of breast cancer is its propensity for distant metastasis to the lung, brain, bone and liver [1,2,3]
Our study corroborates with other studies, which have shown that 20-Hydroxyeicosatetraenoic acid (20-HETE) inhibition reduces invasion in vitro, and angiogenesis and metastasis in vivo by decreasing vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs)-9 expression in human non-small cell lung cancer and MDA-MB-231 breast cancer mouse models [16,17]
Our data demonstrated that 2-Hydroxypropyl beta cyclodextrin (HPßCD)-HET0016 decreases MMP-2 and -9, CD44, and N-cadherin expression, migration and invasion of tumor cells and reduces lung metastasis
Summary
A major challenge in treatment of breast cancer is its propensity for distant metastasis to the lung, brain, bone and liver [1,2,3]. Distant metastasis is the primary cause of death in majority. Of the breast cancer types and its dissemination represents poor prognosis of survival compared to non-metastatic diagnoses [4]. Metastasis involves distinct steps that require detachment of cancer cells from the primary tumor, development of an aggressive phenotype, subsequent survival in transit, cooption on stroma of distant organs, formation of micro metastases, and full colonization [6]. Intercommunication between cells is steered by tangled and dynamic network of cytokines, chemokines, growth factors, inflammatory and matrix remodeling enzymes against a background of major perturbations to the physical and chemical properties of the tissue [7]
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