Abstract
Simple SummaryAngiogenesis is an essential event for the progression of solid tumors and is promoted by angiogenic cytokines released in the tumor microenvironment by neoplastic and stromal cells. Over the last 20 years, the role of the microenvironment and the implication of several angiogenic factors in tumorigenesis of solid and hematological neoplasms have been widely studied. The tumor microenvironment has also been well-defined for thyroid cancer, clarifying the importance of angiogenesis in cancer progression, spread, and metastasis. Furthermore, recent studies have evaluated the association of circulating angiogenic factors with the clinical outcomes of differentiated thyroid cancer, potentially providing noninvasive, low-cost, and safe tests that can be used in screening, diagnosis, and follow-up. In this review, we highlight the mechanisms of action of these proangiogenic factors and their different molecular pathways, as well as their applications in the treatment and prognosis of thyroid cancer.Thyroid cancer is the most common endocrine malignancy, with a typically favorable prognosis following standard treatments, such as surgical resection and radioiodine therapy. A subset of thyroid cancers progress to refractory/metastatic disease. Understanding how the tumor microenvironment is transformed into an angiogenic microenvironment has a role of primary importance in the aggressive behavior of these neoplasms. During tumor growth and progression, angiogenesis represents a deregulated biological process, and the angiogenic switch, characterized by the formation of new vessels, induces tumor cell proliferation, local invasion, and hematogenous metastases. This evidence has propelled the scientific community’s effort to study a number of molecular pathways (proliferation, cell cycle control, and angiogenic processes), identifying mediators that may represent viable targets for new anticancer treatments. Herein, we sought to review angiogenesis in thyroid cancer and the potential role of proangiogenic cytokines for risk stratification of patients. We also present the current status of treatment of advanced differentiated, medullary, and poorly differentiated thyroid cancers with multiple tyrosine kinase inhibitors, based on the rationale of angiogenesis as a potential therapeutic target.
Highlights
Thyroid cancers are the most common endocrine malignancies and have been shown to be one of the fastest-growing malignancies worldwide over the past two decades [1,2,3]
Tumor-associated macrophages (TAMs) contribute to angiogenesis of tumors with an increased production of proangiogenic factors, such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and basic fibroblast growth factor, and produce a high amount of matrix metalloproteases (MMPs), which are responsible for ECM remodeling and facilitate tumor cells spread and invasion [28,29]
VEGF is a member of a family of six structurally related proteins, namely, VEGF-A, -B, -C, -D, -E, and PDGF; these act by interacting with their relative receptors, which are differentially expressed in various cell types [41,65].The VEGF receptors are differentially implicated in angiogenesis stimulation (VEGF-A, -E/VEGFR-2-neuropilin (NRP)-1, -2), or lymphangiogenesis (VEGF-C, -D/VEGFR-2, -3) [41,66,67]
Summary
Thyroid cancers are the most common endocrine malignancies and have been shown to be one of the fastest-growing malignancies worldwide over the past two decades [1,2,3]. Traditional tissue biopsies are somewhat invasive, create discomfort to the patients, and are burdened by contamination from normal tissue and sampling errors [13] Another area where biomarkers are lacking is the identification of disease persistence after surgery/medical therapy and the ability to distinguish between complete response after treatment or recurrence of disease [13]. Angiogenesis is an essential event for the progression of solid tumors and is promoted by angiogenic cytokines released in the tumor microenvironment by tumor and stromal cells, and can be found and measured out with a serum assay in terms of circulating angiogenic factors [14] This is a noninvasive, inexpensive, and safe test that can be potentially used in screening, diagnosis, and follow-up of thyroid cancer patients. The potential role of proangiogenic cytokines for risk stratification of patients with thyroid cancer will be addressed, as well as the individuation of angiogenesis as a potential therapeutic target
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