JRC, Medical Research Company, Osaka, Japan.
National Center for Microscopy and Imaging Research, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Adv Exp Med Biol. 2020;1225:19-29. doi: 10.1007/978-3-030-35727-6_2.
In the past, cancer development was studied in terms of genetic mutations acquired in cancer cells at each stage of the development. We present an emerging model for cancer development in which the tumor microenvironment (TME) plays an integral part. In this model, the tumor development is initiated by a slowly growing nearly homogeneous colony of cancer cells that can evade detection by the cell's innate mechanism of immunity such as natural killer (NK) cells (first stage; colonization). Subsequently, the colony develops into a tumor filled with lymphocytes and stromal cells, releasing pro-inflammatory cytokines, growth factors, and chemokines (second stage; lymphocyte infiltration). Cancer progression proceeds to a well-vesiculated silent tumor releasing no inflammatory signal, being nearly devoid of lymphocytes (third stage; silenced). Eventually some cancer cells within a tumor undertake epithelial-to-mesenchymal transition (EMT), which leads to cancer metastasis (fourth stage; EMT). If a circulating metastasized cancer cell finds a niche in a new tissue and evades detection by NK cells, it can establish a new colony in which very few stromal cells are present (fifth stage; metastasis), which is much like a colony at the first stage of development. At every stage, cancer cells influence their own TME, and in turn, the TME influences the cancer cells contained within, either by direct interaction between cancer cells and stromal cells or through exchange of cytokines. In this article, we examine clinical findings and animal experiments pertaining to this paradigm-shifting model and consider if, indeed, some aspects of cancer development are governed solely by the TME.
在过去，癌症的发展是通过研究癌症细胞在其发展的每个阶段所获得的基因突变来研究的。我们提出了一个癌症发展的新模型，其中肿瘤微环境（TME）起着不可或缺的作用。在这个模型中，肿瘤的发展是由一个缓慢生长的、几乎同质的癌细胞簇引发的，这些癌细胞可以逃避细胞固有免疫机制的检测，如自然杀伤（NK）细胞（第一阶段；定植）。随后，这个细胞簇发展成一个充满淋巴细胞和基质细胞的肿瘤，释放促炎细胞因子、生长因子和趋化因子（第二阶段；淋巴细胞浸润）。癌症的进展进入一个高度包裹的沉默肿瘤，不释放炎症信号，几乎没有淋巴细胞（第三阶段；沉默）。最终，肿瘤内的一些癌细胞会发生上皮间质转化（EMT），导致癌症转移（第四阶段；EMT）。如果肿瘤内的一个循环转移癌细胞在新组织中找到了一个栖息地，并逃避了 NK 细胞的检测，它就可以在其中建立一个新的殖民地，其中很少有基质细胞存在（第五阶段；转移），这非常类似于发育第一阶段的殖民地。在每个阶段，癌细胞都会影响其自身的 TME，反过来，TME 也会影响其中的癌细胞，这种影响可以通过癌细胞与基质细胞之间的直接相互作用，也可以通过细胞因子的交换来实现。在本文中，我们检查了与这一范式转变模型相关的临床发现和动物实验，并考虑了是否事实上，癌症发展的某些方面仅由 TME 决定。
