*Review* **Prognostic and Therapeutic Role of Angiogenic Microenvironment in Thyroid Cancer**

**Assunta Melaccio 1,†, Lucia Ilaria Sgaramella 2,†, Alessandro Pasculli 2,† , Giovanna Di Meo 2, Angela Gurrado 2, Francesco Paolo Prete 2, Angelo Vacca <sup>1</sup> , Roberto Ria <sup>1</sup> and Mario Testini 2,\***


**Simple Summary:** Angiogenesis 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.

**Abstract:** 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.

**Keywords:** thyroid carcinoma; angiogenic microenvironment; prognostic factors; antiangiogenic therapy; therapeutic target; tumor microenvironment; tumor behavior; proliferation pathways; cell cycle control pathways; angiogenesis process

**Citation:** Melaccio, A.; Sgaramella, L.I.; Pasculli, A.; Di Meo, G.; Gurrado, A.; Prete, F.P.; Vacca, A.; Ria, R.; Testini, M. Prognostic and Therapeutic Role of Angiogenic Microenvironment in Thyroid Cancer. *Cancers* **2021**, *13*, 2775. https://doi.org/10.3390/ cancers13112775

Academic Editors: Fabio Medas and Pier Francesco Alesina

Received: 28 April 2021 Accepted: 31 May 2021 Published: 3 June 2021

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