Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment Prospects and Obstacles for Therapeutic Targeting of Function-enabling Stromal Cell Types
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment Prospects and Obstacles for Therapeutic Targeting of Function-enabling Stromal Cell Types
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通讯作者：
D. Hanahan;L. Coussens
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作者：
D. Hanahan;L. Coussens
突变破坏的癌（干）细胞是肿瘤发展和进展的驱动力。然而，这些转化的细胞不能单独完成。表面上正常的组织和骨髓来源的（基质）细胞的集合体被募集以构成致瘤微环境。癌症的大多数特征通过基质细胞类型和独特的亚细胞类型的库的贡献而在不同程度上得以实现和维持。它们对标志性能力的贡献功能越来越被人们所理解，与肿瘤癌细胞的相互通信也是如此，肿瘤癌细胞介导了它们的招募、激活、编程和持久性。这种增强的理解为抗癌治疗提供了有趣的新靶点。在过去的四十年中，癌症研究的首要焦点一直是恶性癌细胞，试图了解显性癌基因和肿瘤抑制基因，其各自的激活/上调或功能丧失用于赋予正常细胞异常特性，从而有助于它们转化为形成恶性肿瘤基础的癌细胞。新的工具和新的数据不断丰富我们对恶性细胞特性和遗传畸变的知识和见解，这些特性和遗传畸变赋予癌症作为一种慢性疾病的增殖基础。全基因组重测序和全基因组的遗传学和转录谱分析呈现出大量新数据，人们对将其提炼成清晰的机制寄予厚望，同时也面临着挑战，这些机制反过来又可以转化为更有效的疗法。除了极少数例外，今天对大多数形式的人类癌症的治疗仍然不完全有效和短暂，尽管知道驱动致癌基因和关键的致癌信号通路适合于靶向治疗的药理学干预。事实上，如果将人类癌症的多样性纳入其中，那么蒸馏的挑战将更加艰巨，这些癌症源自不同组织和器官中的独特细胞，具有肿瘤发展和进展、致癌突变、预后和对治疗的反应的可变参数。癌症标志（Hanahan和温伯格，2000）被认为是为癌细胞基因型和表型的这种多样性和差异提出了一个概念上的合理性-一个潜在的共同性，假定癌症的谱反映了对潜在不法细胞的相同挑战的不同解决方案，能够绕过在高等生物体中进化的内在障碍和保护功能，以防止未经授权的，慢性细胞增殖第二个前提是肿瘤微环境（TME）的重要性现在越来越被接受，体现在癌细胞不表现出疾病的概念中。
Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment , activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy. The overarching focus of cancer research for the past four decades has been on the malignant cancer cell, seeking to understand the dominant oncogenes and tumor suppressor genes whose respective activation/upregulation or loss of function serve to impart aberrant properties on normal cells, thus contributing to their transformation into the cancerous cells that form the basis for malignancy. New tools and new data have continued to enrich our knowledge and insights into properties of malignant cells and the genetic aberrations that endow the proliferative foundation of cancer as a chronic disease. Whole-genome resequencing and genome-wide epige-netic and transcriptional profiling are presenting an avalanche of new data, with great expectations and concomitant challenges to distill it into a clarity of mechanism that can, in turn, be translated into more effective therapies. With rare exception, today's therapies for most forms of human cancer remain incompletely effective and transitory, despite knowledge of driving oncogenes and crucial oncogenic signaling pathways amenable to pharmacological intervention with targeted therapies. The challenge of distillation is, in fact, even more daunting if one incorporates the diversity of human cancers arising from distinctive cells of origin in different tissues and organs, with variable parameters of tumor development and progression, oncogenic mutation, prognosis, and response to therapy. The hallmarks of cancer (Hanahan and Weinberg, 2000) were conceived to suggest a conceptual rationale—an underlying commonality—for this diversity and disparity in cancer cell genotypes and phenotypes, positing that the spectrum of cancers reflects different solutions to the same challenge to a prospective outlaw cell, being able to circumvent the intrinsic barriers and protective functions that have evolved in higher organisms to prevent unauthorized, chronic cell proliferation. A second premise was the now-increasingly accepted importance of the tumor microenvironment (TME), embodied in the concept that cancer cells do not manifest the disease …