Mechanisms and Regulation of Invasion in Thyroid Cancer

Michael W. Yeh, MD ■ Michael J. Demeure, MD ■ Kevin Packman, MD

The management of invasive and metastatic disease represents the single greatest challenge in the treatment of cancer today.1 Although most differentiated thyroid cancers are adequately treated with surgical resection and radioiodine therapy, poorly differentiated and undifferentiated cancers, whose behavior is characterized by aggressive local invasion and metastasis, are often lethal.2 Furthermore, metastatic foci of differentiated thyroid cancer frequently fail to take up sufficient quantities of radioiodine to be successfully ablated.3 Because conventional chemotherapy and radiotherapy have yielded disappointing results in the treatment of aggressive thyroid cancers,4-5 new strategies for inhibiting tumor growth, invasion, and angiogenesis (itself an invasive process) are needed.

Thyroid nodules are a common problem, affecting roughly 4% of the U.S. population. Fine-needle aspiration, which has emerged as the single most useful test in the evaluation of nodular thyroid disease, is useful in distinguishing between benign and malignant growths in most cases.6 Difficulty arises in the work-up of follicular and Hiirthle cell neoplasms, which can currently be diagnosed as malignant only after permanent pathologic examination reveals capsular or vascular invasion, or both.7 Similar issues arise in the management of adrenal neoplasms and neuroendocrine tumors of the gastrointestinal tract.8-83 Because only about 15% of follicular thyroid neoplasms are eventually proved to be malignant, many patients undergo surgery unnecessarily. Thus, it is hoped that an increased understanding of the invasion process in follicular thyroid cancer (FTC) may allow the development of reliable cytologic or molecular indicators of tumor behavior.

Histologically, invasion through the epithelial basement membrane marks the progression from carcinoma in situ to carcinoma. The invasion process is thought to involve at least three major components: (1) adhesion to the extracellular matrix, (2) proteolysis of the collagen barrier, and (3) migration into adjacent tissues (Fig. 32-1).9 These steps, however, are interlinked and inseparable. A number of intracellular and extracellular signaling molecules have been implicated in the positive and negative regulation of invasive behavior. These molecules have also linked the regulators and effectors of invasion to the related processes of inflammation and angiogenesis.10"12 This chapter is intended to describe some of the many cellular mechanisms that appear to be associated with invasion in thyroid cancer and human cancers as a whole.

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