Human Thyroid Cancers Preclinical and Translational Research Program, Division of Experimental Pathology, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Center for Vascular Biology Research (CVBR), Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Thyroid. 2023 Jul;33(7):835-848. doi: 10.1089/thy.2022.0597.
Anaplastic thyroid carcinoma (ATC) is a rapidly fatal cancer with a median survival of a few months. Enhanced therapeutic options for durable management of ATC will rely on an understanding of genetics and the role of the tumor microenvironment. The prognosis for patients with ATC has not improved despite more detailed scrutiny of underlying tumor genetics. Pericytes in the microenvironment play a key evasive role for thyroid carcinoma (TC) cells. Lenvatinib improves outcomes in patients with radioiodine-refractory well-differentiated TC. In addition to the unclear role of pericytes in ATC, the effect and mechanism of lenvatinib efficacy on ATC have not been sufficiently elucidated. We assessed pericyte enrichment in ATC. We determined the effect of lenvatinib on ATC cell growth cocultured with pericytes and in a xenograft mouse model from human -ATC-derived cells coimplanted with pericytes. ATC samples were significantly enriched in pericytes compared with normal thyroid samples. -ATC-derived cells were resistant to lenvatinib treatment shown by a lack of suppression of MAPK and Akt pathways. Moreover, lenvatinib increased CD47 protein (thrombospondin-1 [TSP-1] receptor) levels over time vs. vehicle. TSP-1 levels were downregulated upon lenvatinib at late vs. early time points. Critically, ATC cells, when cocultured with pericytes, showed increased sensitivity to this therapy and ultimately decreased number of cells. The coimplantation of ATC cells with pericytes increased ATC growth and did not downregulate TSP-1 in the microenvironment . Pericytes are enriched in ATC samples. Lenvatinib showed inhibitory effects on -ATC cells in the presence of pericytes. The presence of pericytes could be crucial for effective lenvatinib treatment in patients with ATC. Degree of pericyte abundance may be an attractive prognostic marker in assessing pharmacotherapeutic options. Effective durable management of ATC will rely on an understanding not only of genetics but also on the role of the tumor microenvironment.
间变性甲状腺癌（ATC）是一种迅速致命的癌症，中位生存期为数月。增强对 ATC 的持久管理的治疗选择将依赖于对遗传学和肿瘤微环境的作用的理解。尽管对潜在肿瘤遗传学进行了更详细的检查，但是 ATC 患者的预后并没有改善。微环境中的周细胞在甲状腺癌（TC）细胞中起着关键的逃避作用。仑伐替尼可改善放射性碘难治性分化良好 TC 患者的预后。除了周细胞在 ATC 中的作用不明确外，仑伐替尼对 ATC 的疗效及其机制尚未充分阐明。我们评估了 ATC 中的周细胞富集。我们确定了仑伐替尼对与周细胞共培养的 ATC 细胞生长的影响，以及在与人 ATC 衍生细胞共植入周细胞的异种移植小鼠模型中的作用。与正常甲状腺样本相比，ATC 样本中明显富集了周细胞。 -ATC 衍生细胞对仑伐替尼治疗具有抗性，MAPK 和 Akt 途径的抑制作用缺乏。此外，与载体相比，仑伐替尼随时间推移增加了 CD47 蛋白（血小板反应蛋白 1[TSP-1]受体）的水平。TSP-1 水平在晚期而非早期时间点随着仑伐替尼的作用而降低。重要的是，当与周细胞共培养时，ATC 细胞对这种治疗方法的敏感性增加，最终细胞数量减少。共植入 ATC 细胞和周细胞增加了 ATC 的生长，并且没有下调微环境中的 TSP-1。周细胞在 ATC 样本中丰富。在存在周细胞的情况下，仑伐替尼对 -ATC 细胞显示出抑制作用。周细胞的存在对于 ATC 患者的有效仑伐替尼治疗可能至关重要。周细胞丰度的程度可能是评估药物治疗选择的有吸引力的预后标志物。不仅要了解遗传学，还要了解肿瘤微环境的作用，才能有效地对 ATC 进行持久管理。
