The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer

Abstract

Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients.

RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation

“…This interaction results in the subsequent STAT3 activation to promote human medullary cancer cell growth (Figure 5). Considering the malignancy of medullary thyroid cancer, patients with advanced and metastasized medullary thyroid cancer are difficult to treat since tumor cells do not respond to chemotherapeutic treatment and external radiation [63][64][65]. Therefore, targeting of CDK5 might be a therapeutic approach for the treatment of human medullary thyroid cancer in the near future.…”

Dynamic Cancer Cell Heterogeneity: Diagnostic and Therapeutic Implications

“…ATC may derive from both papillary and follicular carcinomas or from normal thyroid tissue, by qualitative, as of yet undefined mechanism(s), although a separate fetal origin has been suggested by Takano et al [ 13 , 116 ]. This fetal cell carcinogenesis hypothesis, in which mutational events may occur in thyroid precursors at different stages of differentiation, has been extended to all TC subtypes [ 117 ]. However, it has been widely observed that most of the patients with ATC have previous or concomitant differentiated thyroid carcinomas, and an “anaplastic transformation” from the differentiated carcinoma to the anaplastic carcinoma is sometimes clinically observed.…”

Thyroid Cancer Stem-Like Cells: From Microenvironmental Niches to Therapeutic Strategies

“…According to the classic multistep carcinogenesis model ( Figure 1 A), TC cells arise from the gradual accumulation of genetic alterations within normal thyroid epithelial cells, leading to uncontrolled proliferation and an invasive phenotype [ 24 , 25 ]. Thus, PTC and FTC are the results of randomly occurring genetic alterations, such as BRAF and RAS point mutations or the more complex RET/PTC and PAX8/PPARγ rearrangements.…”

“…In this perspective, some authors hypothesized that TC may be a CSC-driven disease [ 26 , 35 , 36 ], with only a subset of cancer cells that possess high tumorigenic activity, with increased ability to self-renew and produce progenitor cells that can reconstitute and sustain tumor growth [ 1 ] ( Figure 1 C). The transition of stem cells into mature cells is stimulated by growth factors and cytokines present in the microenvironment outside the stem niche [ 25 ]. According to this view, CSCs may originate from either normal stem cells through a transformation process or from differentiated cancer cells as the result of a dedifferentiation process [ 35 ].…”