肿瘤中的细胞并不都是一样的，这些肿瘤细胞在生长和患者治疗的整个阶段会产生不同的遗传突变，同时也会表现出不同的特性，这些差异就使得肿瘤非常难以对付，从而往往会产生因许多恶性肿瘤细胞而导致的肿瘤耐药性的发生。近日，发表于国际杂志Cancer Research上的研究论文中，来自莫非特癌症研究中心的研究人员通过利用一种数学模型，对不同肿瘤细胞的特性进行了分析，相关研究或为后期开发特殊的癌症治疗手段提供帮助。

　　研究者Mark Robsertson-Tessi博士表示，相比正常组织而言，许多肿瘤都会表现出不同的代谢行为，其会消耗较多的葡萄糖，同时产生酸作为副产品，进而制造一种酸性环境，这样一来肿瘤细胞就可以更好地在酸性环境中生长，并且促进癌细胞的侵袭和扩散。

　　研究者想去研究确定肿瘤细胞代谢特性的差异是否会影响癌症的生长和疗法，于是他们就开发了一种数学模型，这种模型可以检测肿瘤细胞代谢和其周围组织之间的相互作用。研究者发现肿瘤组织中心的细胞可以进化产生较多的酸，并且相比肿瘤外源细胞而言，中心的肿瘤细胞会进行较多的葡萄糖代谢，这就会促进中心的肿瘤细胞变得更具有侵略性，侵略性的细胞就会慢慢移动到肿瘤边缘开始进行扩散。

　　研究者表示，我们想知道是否治疗性的疗法可以影响肿瘤细胞的代谢和行为，研究发现当肿瘤异质性较高时，利用疗法治疗肿瘤就会促进肿瘤边缘的细胞死亡，而使得肿瘤中心的侵略性细胞变得更加具有侵袭性。更为重要的是，研究者还发现一种抗血管生成的癌症疗法在临床中失败的可能性原因，抗血管生成疗法会阻断肿瘤血管的生成，而血管是肿瘤营养来源的关键，最初研究认为这种疗法会促进肿瘤细胞饿死，抑制其生长，而研究者发现，抗血管生成的制剂实际上会促进肿瘤中心的细胞变得更加具有侵袭性。

　　本文研究开发的数学模型为后期科学家们揭示并不能通过简单基因和周围肿瘤环境来进行研究的肿瘤的发生机制提供了新的思路，研究者认为仅仅通过将数学模型和计算机模型相结合就可以加快构建癌症发展过程中“基因中心观点”和“肿瘤微环境关键”之间的桥梁，从而为揭示癌症发生的新机制提供新的见解和思路。

　　doi:10.1158/0008-5472.CAN-14-1428

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　　Impact of Metabolic Heterogeneity on Tumor Growth, Invasion, and Treatment Outcomes

　　Mark Robertson-Tessi1,*, Robert J. Gillies2, Robert A. Gatenby1,2, and Alexander R.A. Anderson1

　　Histopathologic knowledge that extensive heterogeneity exists between and within tumors has been confirmed and deepened recently by molecular studies. However, the impact of tumor heterogeneity on prognosis and treatment remains as poorly understood as ever. Using a hybrid multiscale mathematical model of tumor growth in vascularized tissue, we investigated the selection pressures exerted by spatial and temporal variations in tumor microenvironment and the resulting phenotypic adaptations. A key component of this model is normal and tumor metabolism and its interaction with microenvironmental factors. The metabolic phenotype of tumor cells is plastic, and microenvironmental selection leads to increased tumor glycolysis and decreased pH. Once this phenotype emerges, the tumor dramatically changes its behavior due to acid-mediated invasion, an effect that depends on both variations in the tumor cell phenotypes and their spatial distribution within the tumor. In early stages of growth, tumors are stratified, with the most aggressive cells developing within the interior of the tumor. These cells then grow to the edge of the tumor and invade into the normal tissue using acidosis. Simulations suggest that diffusible cytotoxic treatments, such as chemotherapy, may increase the metabolic aggressiveness of a tumor due to drug-mediated selection. Chemotherapy removes the metabolic stratification of the tumor and allows more aggressive cells to grow toward blood vessels and normal tissue. Antiangiogenic therapy also selects for aggressive phenotypes due to degradation of the tumor microenvironment, ultimately resulting in a more invasive tumor. In contrast, pH buffer therapy slows down the development of aggressive tumors, but only if administered when the tumor is still stratified. Overall, findings from this model highlight the risks of cytotoxic and antiangiogenic treatments in the context of tumor heterogeneity resulting from a selection for more aggressive behaviors. Cancer Res; 75(8); 1567–79. 2015 AACR.