Institute of Pathology and Molecular Immunology of the University of Porto (Ipatimup), Porto, Portugal.
Institute of Investigation and Innovation in Health (i3S), Porto, Portugal.
Adv Exp Med Biol. 2019;1139:83-103. doi: 10.1007/978-3-030-14366-4_5.
In the last 20 years, the conventional view of breast cancer as a homogeneous collection of highly proliferating malignant cells was totally replaced by a model of increased complexity, which points out that breast carcinomas are tissues composed of multiple populations of transformed cells. A large diversity of host cells and structural components of the extracellular matrix constitute the mammary tumour microenvironment, which supports its growth and progression, where individual cancer cells evolve with cumulative phenotypic and genetic heterogeneity. Moreover, contributing to this heterogeneity, it has been demonstrated that breast cancers can exhibit a hierarchical organization composed of tumour cells displaying divergent lineage biomarkers and where, at the apex of this hierarchy, some neoplastic cells are able to self-renew and to aberrantly differentiate. Breast cancer stem cells (BCSCs), as they were entitled, not only drive tumourigenesis, but also mediate metastasis and contribute to therapy resistance.Recently, adding more complexity to the system, it has been demonstrated that BCSCs maintain high levels of plasticity, being able to change between mesenchymal-like and epithelial-like states in a process regulated by the tumour microenvironment. These stem cell state transitions play a fundamental role in the process of tumour metastasis, as well as in the resistance to putative therapeutic strategies to target these cells. In this chapter, it will be mainly discussed the emerging knowledge regarding the contribution of BCSCs to tumour heterogeneity, their plasticity, and the role that this plasticity can play in the establishment of distant metastasis. A major focus will also be given to potential clinical implications of these discoveries in breast cancer recurrence and to possible BCSC targeted therapeutics by the use of specific biomarkers.
在过去的 20 年中，乳腺癌作为一种高度增殖的恶性细胞同质集合的传统观点已被完全取代，取而代之的是一种更为复杂的模型，该模型指出乳腺癌是由多种转化细胞组成的组织。大量宿主细胞和细胞外基质的结构成分构成了乳腺肿瘤微环境，它支持其生长和进展，其中单个癌细胞会随着累积的表型和遗传异质性而进化。此外，研究表明，乳腺癌可以表现出一种分层组织，由具有不同谱系生物标志物的肿瘤细胞组成，在这个层次结构的顶端，一些肿瘤细胞能够自我更新并异常分化。乳腺癌干细胞（BCSCs），正如它们的名称所示，不仅驱动肿瘤发生，还介导转移，并有助于治疗耐药性。最近，该系统的复杂性进一步增加，研究表明 BCSCs 保持着高度的可塑性，能够在肿瘤微环境调控的过程中在间充质样和上皮样状态之间转换。这些干细胞状态的转变在肿瘤转移过程中起着至关重要的作用，以及对针对这些细胞的潜在治疗策略的耐药性中也起着至关重要的作用。在本章中，将主要讨论关于 BCSCs 对肿瘤异质性、其可塑性的贡献的新认识，以及这种可塑性在建立远处转移中的作用。还将重点关注这些发现对乳腺癌复发的潜在临床意义，以及通过使用特定的生物标志物对 BCSC 进行靶向治疗的可能性。
