Department of Pathology, Anatomy and Cell Biology and the Clinical and Translational Research Center of Excellence, Meharry Medical College, Nashville, TN 37208, USA.
Department of Graduate Medical Education, Scripps Mercy Hospital, San Diego, CA 92103, USA.
Oncotarget. 2024 Oct 11;15:726-740. doi: 10.18632/oncotarget.28658.
Cancer dormancy followed by recurrence remains an enigma in cancer biology. Since both local and systemic recurrences are thought to emanate from dormant micrometastasis which take origin from lymphovascular tumor emboli we wondered whether the process of dormancy might initiate within lymphovascular emboli. This study combines experimental studies with a patient-derived xenograft (PDX) of inflammatory breast cancer (Mary-X) that spontaneously forms spheroids and budding lymphovascular tumor emboli with observational studies utilizing tissue microarrays (TMAs) of human breast cancers. In the experimental studies, Mary-X during both lymphovascular emboli formation and spheroidgenesis exhibited decreased proliferation, a G/G cell cycle arrest and decreased mTOR signaling. This induction of dormancy required calpain-mediated E-cadherin proteolysis and was mediated by decreased P13K signaling, resulting in decreased mTOR activity. In observational human breast cancer studies, increased E-cadherin immunoreactivity due to increased E-cad/NTF-1 but both decreased Ki-67 and mTOR activity was observed selectively and differentially within the lymphovascular tumor emboli. Both our experimental as well as observational studies indicate that lymphovascular tumor emboli and their spheroid equivalent initiate dormancy through these pathways.
癌症休眠后再复发仍然是癌症生物学中的一个谜。由于局部和全身复发都被认为起源于休眠的微转移灶，而这些微转移灶起源于淋巴血管肿瘤栓子，我们想知道休眠过程是否可能发生在淋巴血管栓子内。这项研究结合了实验研究和源自炎性乳腺癌（Mary-X）的患者源性异种移植物（PDX），该 PDX 自发形成球体和芽生淋巴血管肿瘤栓子，以及利用人类乳腺癌组织微阵列（TMA）进行的观察性研究。在实验研究中，Mary-X 在淋巴血管栓子形成和球体发生过程中表现出增殖减少、G1/G0 细胞周期停滞和 mTOR 信号降低。这种休眠的诱导需要钙蛋白酶介导的 E-钙黏蛋白蛋白水解，并且通过降低的 PI3K 信号转导来介导，导致 mTOR 活性降低。在观察性的人类乳腺癌研究中，观察到由于 E-cad/NTF-1 的增加而导致的 E-钙黏蛋白免疫反应性增加，但 Ki-67 和 mTOR 活性均降低，仅选择性和差异性地存在于淋巴血管肿瘤栓子内。我们的实验和观察性研究均表明，淋巴血管肿瘤栓子及其球体等价物通过这些途径启动休眠。
