Abstract
Metastasis represents a serious complication in the treatment of cancer. Flavonoids are plant secondary metabolites exerting various health beneficiary effects. The effects of flavonoids against cancer are associated not only with early stages of the cancer process, but also with cancer progression and spread into distant sites. Flavonoids showed potent anti-cancer effects against various cancer models in vitro and in vivo, mediated via regulation of key signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of epithelial-mesenchymal transition or regulatory molecules such as MMPs, uPA/uPAR, TGF-β and other contributors of the complex process of metastatic spread. Moreover, flavonoids modulated also the expression of genes associated with the progression of cancer and improved inflammatory status, a part of the complex process involved in the development of metastasis. Flavonoids also documented clear potential to improve the anti-cancer effectiveness of conventional chemotherapeutic agents. Most importantly, flavonoids represent environmentally-friendly and cost-effective substances; moreover, a wide spectrum of different flavonoids demonstrated safety and minimal side effects during long-termed administration. In addition, the bioavailability of flavonoids can be improved by their conjugation with metal ions or structural modifications by radiation. In conclusion, anti-cancer effects of flavonoids, targeting all phases of carcinogenesis including metastatic progression, should be implemented into clinical cancer research in order to strengthen their potential use in the future targeted prevention and therapy of cancer in high-risk individuals or patients with aggressive cancer disease with metastatic potential.
Highlights
The invasion into nearby tissues and the formation of distant metastasis is one of central features of malignancy
The modification of secondary tissue microenvironments to promote metastatic colonization, a mechanism known as pre-metastatic niche, is a result of complex interactions of factors secreted by tumor and tumor-shed extracellular vesicles, with specific surface marker compositions inducing changes such as induction of vascular leakiness, stroma, and extracellular matrix (ECM) remodeling, and the influence on the immune system [14]
Intraperitoneal administration of pectolinarigenin inhibited breast cancer metastasis into lungs in Balb/c mice injected with 4T1 mouse breast cancer cells and suppressed migration and invasion of MCF-7, MDA-MB-231, and 4T1 breast cancer cells in vitro mediated by an inhibition of MMP-2, MMP-9, and p-STAT3 expression and upregulation of tissue inhibitors of metalloproteinases (TIMPs)-2 [69]
Summary
The invasion into nearby tissues and the formation of distant metastasis is one of central features of malignancy. Metastasis represents the primary cause of death of cancer patients. Determining the establishment of metastasis as a result of an interplay between cancer cells of a primary tumor as well as microenvironment of the pre-metastatic site [2] designates them as important targets of anti-metastatic cancer research [3]. Flavonoids modulate signaling pathways during cancer initiation or promotion, but their effects are significant in the processes of cancer progression, including invasiveness of surrounding areas and the formation of distant metastasis [4,5,6]. Targeted applications of anti-cancer agents based on phytochemicals in high-risk individuals for cancer, as well as personalized therapy of patients with a diagnosed highly-aggressive form of malignancy with a tendency to metastasize, would represent a significant shift in cancer research and later oncology practice
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