Burack W Richard, Spence Janice M, Spence John P, Spence Stephen A, Rock Philip J, Shenoy Gautam N, Shultz Leonard D, Bankert Richard B, Bernstein Steven H
Pathology and Laboratory Medicine, University of Rochester, Rochester, NY.
Microbiology and Immunology, State University of New York at Buffalo, Buffalo, NY.
Blood Adv. 2017 Jul 7;1(16):1263-1273. doi: 10.1182/bloodadvances.2017005892. eCollection 2017 Jul 11.
To discern features of non-Hodgkin lymphomas (NHL) that are autonomous from those that are shaped by the tumor environment (TE), we used patient-derived xenografts (PDX) to probe the effects on neoplastic cells of manipulating the TE. Properties of neoplastic cells that are often considered to be autonomous include their relative independence from stromal support, their relative survival and/or proliferation advantages compared with nonneoplastic cells, and their state of differentiation. Prior approaches to creation of PDX models likely select for neoplasms, which are the most capable of engraftment, potentially masking the effects of the TE. To overcome this bias, we developed a robust protocol that rapidly produced xenografts with more than 85% of unselected, cryo-preserved, B-cell NHL specimens, including low-grade tumors such as follicular and marginal zone lymphoma. To discern features that are shaped by the TE, we extensively studied 4 low-grade lymphoma specimens. B-cell engraftment required components of the native TE; specifically, CD4 cells. The relative survival of neoplastic compared with nonneoplastic B cells was not autonomous in 2 specimens; specifically, neoplastic B cells from 2 specimens showed a greater dependence on the TE than normal B cells for engraftment. Furthermore, the differentiation of neoplastic B cells was dependent on the TE; mature B-cell neoplasms converted to plasmacytoma-like lesions in the grafts. These results highlight the central and patient-specific roles of the TE in maintaining the relative survival of neoplastic cells compared with normal cells and in controlling the differentiation of neoplastic cells.
为了辨别非霍奇金淋巴瘤（NHL）中不受肿瘤微环境（TE）影响的特征，我们使用患者来源的异种移植（PDX）来探究操纵TE对肿瘤细胞的影响。通常被认为是自主性的肿瘤细胞特性包括它们相对独立于基质支持、与非肿瘤细胞相比具有相对的生存和/或增殖优势，以及它们的分化状态。先前创建PDX模型的方法可能会选择最能够移植的肿瘤，这可能掩盖了TE的影响。为了克服这种偏差，我们开发了一种可靠的方案，该方案能快速产生异种移植，其中超过85%的标本是未选择的、冷冻保存的B细胞NHL标本，包括滤泡性和边缘区淋巴瘤等低级别肿瘤。为了辨别由TE塑造的特征，我们广泛研究了4个低级别淋巴瘤标本。B细胞移植需要天然TE的成分；具体来说，是CD4细胞。在2个标本中，肿瘤性B细胞与非肿瘤性B细胞相比的相对生存并非自主性的；具体而言，来自2个标本的肿瘤性B细胞在移植时比正常B细胞对TE的依赖性更强。此外，肿瘤性B细胞的分化依赖于TE；成熟B细胞肿瘤在移植物中转化为浆细胞瘤样病变。这些结果突出了TE在维持肿瘤细胞与正常细胞相比的相对生存以及控制肿瘤细胞分化方面的核心和患者特异性作用。
