Johnson Jennifer M, Lai Stephen Y, Cotzia Paolo, Cognetti David, Luginbuhl Adam, Pribitkin Edmund A, Zhan Tingting, Mollaee Mehri, Domingo-Vidal Marina, Chen Yunyun, Campling Barbara, Bar-Ad Voichita, Birbe Ruth, Tuluc Madalina, Martinez Outschoorn Ubaldo, Curry Joseph
Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA.
Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.
Semin Oncol. 2015 Dec;42(6):915-22. doi: 10.1053/j.seminoncol.2015.09.025. Epub 2015 Sep 24.
Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target.
间变性甲状腺癌（ATC）是最具侵袭性的人类癌症之一。调节线粒体代谢的关键信号转导通路在ATC中经常发生改变。我们的目标是通过研究线粒体代谢标志物，特别是单羧酸转运蛋白1（MCT1）和线粒体外膜转位酶成员20（TOMM20），来确定ATC的线粒体代谢表型。通过视觉和Aperio数字评分评估了35个人类甲状腺样本（15例ATC、12例甲状腺乳头状癌[PTC]和8例非癌性甲状腺）和9个ATC小鼠原位异种移植瘤中MCT1和TOMM20的染色模式。在可行的情况下，分别评估癌症相关区域与无癌症证据区域的染色模式。与非癌性甲状腺组织和甲状腺乳头状癌相比，MCT1在人类间变性甲状腺癌中高表达（两者P<0.001）。与非癌性甲状腺组织相比，TOMM20在ATC和PTC中也高表达（两者P<0.01）。与非癌性甲状腺组织相比，在ATC小鼠异种移植瘤中也发现MCT1和TOMM20高表达（P<0.001）。这些异种移植瘤具有高的（13）C-丙酮酸摄取。ATC具有使其区别于PTC和非癌性甲状腺组织的代谢特征，包括MCT1和TOMM20的高表达。PTC中MCT1表达低，非癌性甲状腺组织中MCT1和TOMM20表达均低。这项工作表明，MCT1阻断可能特异性地靶向ATC细胞，为新药靶点提供了机会。
