The tumor microenvironment shapes hallmarks of mature B-cell malignancies.
The tumor microenvironment shapes hallmarks of mature B-cell malignancies.
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作者：
Shain KH;Dalton WS;Tao J
B细胞肿瘤的发生是由许多已知和未知的遗传异常引起的，包括通常作为细胞增殖或细胞存活决定因素的基因非随机易位到与活性免疫球蛋白重链增强子元件并列的区域、染色体非整倍性、进一步影响致癌信号传导的体细胞突变以及肿瘤抑制基因杂合性的丧失。然而，重要的是要认识到，即使在遗传性疾病的情况下，B 细胞/浆细胞肿瘤微环境 (TME) 对恶性转化和发病机制也有显着影响。十多年前，我们提出了细胞粘附介导的耐药性的概念，以描述一种 TME 介导的耐药性，可以保护造血肿瘤细胞免受多种疗法的初始影响。在此期间，人们越来越认识到，TME还通过持续生长/增殖、自我更新能力、免疫逃避、迁移和侵袭以及对许多B细胞恶性肿瘤（包括套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、华氏巨球蛋白血症、慢性淋巴细胞白血病和多发性骨髓瘤）的细胞死亡的抵抗力，促进肿瘤的发生和进展。在这篇综述中，我们提出 TME 和肿瘤是双向信号网络共同进化的结果。因此，TME 是一个重要的靶点，应被视为肿瘤进展和药物反应不可或缺的一部分。
B-cell tumorigenesis results from a host of known and unknown genetic anomalies, including non-random translocations of genes that normally function as determinants of cell proliferation or cell survival to regions juxtaposed to active immunoglobulin heavy chain enhancer elements, chromosomal aneuploidy, somatic mutations that further affect oncogenic signaling and loss of heterozygosity of tumor-suppressor genes. However, it is critical to recognize that even in the setting of a genetic disease, the B-cell/plasma cell tumor microenvironment (TME) contributes significantly to malignant transformation and pathogenesis. Over a decade ago, we proposed the concept of cell adhesion-mediated drug resistance to delineate a form of TME-mediated drug resistance that protects hematopoietic tumor cells from the initial effect of diverse therapies. In the interim, it has been increasingly appreciated that TME also contributes to tumor initiation and progression through sustained growth/proliferation, self-renewal capacity, immune evasion, migration and invasion as well as resistance to cell death in a host of B-cell malignancies, including mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia, chronic lymphocytic leukemia and multiple myeloma. Within this review, we propose that TME and the tumor co-evolve as a consequence of bidirectional signaling networks. As such, TME represents an important target and should be considered integral to tumor progression and drug response.