European Institute of Oncology (IEO) IRCCS, Via Ripamonti 435, 20141 Milan, Italy.
Department of Oncology and Hemato-Oncology, University of Milan, Via Santa Sofia 9, 20142 Milan, Italy.
Int J Mol Sci. 2022 Jun 3;23(11):6271. doi: 10.3390/ijms23116271.
Metastatic disease represents the primary cause of breast cancer (BC) mortality, yet it is still one of the most enigmatic processes in the biology of this tumor. Metastatic progression includes distinct phases: invasion, intravasation, hematogenous dissemination, extravasation and seeding at distant sites, micro-metastasis formation and metastatic outgrowth. Whole-genome sequencing analyses of primary BC and metastases revealed that BC metastatization is a non-genetically selected trait, rather the result of transcriptional and metabolic adaptation to the unfavorable microenvironmental conditions which cancer cells are exposed to (e.g., hypoxia, low nutrients, endoplasmic reticulum stress and chemotherapy administration). In this regard, the latest multi-omics analyses unveiled intra-tumor phenotypic heterogeneity, which determines the polyclonal nature of breast tumors and constitutes a challenge for clinicians, correlating with patient poor prognosis. The present work reviews BC classification and epidemiology, focusing on the impact of metastatic disease on patient prognosis and survival, while describing general principles and current in vitro/in vivo models of the BC metastatic cascade. The authors address here both genetic and phenotypic intrinsic heterogeneity of breast tumors, reporting the latest studies that support the role of the latter in metastatic spreading. Finally, the review illustrates the mechanisms underlying adaptive stress responses during BC metastatic progression.
转移性疾病是乳腺癌（BC）死亡的主要原因，但它仍然是这种肿瘤生物学中最神秘的过程之一。转移进展包括不同的阶段：侵袭、血管内渗透、血源性扩散、血管外渗和在远处部位播种、微转移形成和转移生长。对原发性 BC 和转移灶的全基因组测序分析表明，BC 转移是一种非遗传选择的特征，而不是癌细胞对其暴露的不利微环境条件（例如缺氧、低营养、内质网应激和化疗）进行转录和代谢适应的结果。在这方面，最新的多组学分析揭示了肿瘤内表型异质性，这决定了乳腺癌的多克隆性质，这对临床医生来说是一个挑战，与患者预后不良相关。本文综述了 BC 的分类和流行病学，重点介绍了转移性疾病对患者预后和生存的影响，同时描述了 BC 转移级联的一般原则和当前的体外/体内模型。作者在这里讨论了乳腺癌的遗传和表型固有异质性，报告了支持后者在转移扩散中作用的最新研究。最后，综述说明了在 BC 转移进展过程中适应性应激反应的机制。
