The CXCL12/CXCR7 signaling axis, isoforms, circadian rhythms, and tumor cellular composition dictate gradients in tissue

Chemokine CXCL12 gradients drive chemotaxis in a CXCR4-dependent mechanism and have been implicated in cancer metastasis. While CXCL12 gradients are typically studied in organized, defined environments, the tumor microenvironment is disorganized. In vivo, CXCL12 gradients depend on many factors: the number and arrangement of cells secreting and degrading CXCL12, isoform-dependent binding to the extracellular matrix, diffusion, and circadian fluctuations. We developed a computational model of the tumor microenvironment to simulate CXCL12 gradient dynamics in disorganized tissue. There are four major findings from the model. First, CXCL12-β and -γ form higher magnitude (steeper) gradients compared to CXCL12-α. Second, endothelial CXCR7+ cells regulate CXCL12 gradient direction by controlling concentrations near but not far from the vasculature. Third, the magnitude and direction of CXCL12 gradients are dependent on the local composition of secreting and scavenging cells within the tumor. We theorize that “micro-regions” of cellular heterogeneity within the tumor are responsible for forming strong gradients directed into the blood. Fourth, CXCL12 circadian fluctuations influence gradient magnitude but not direction. Our simulations provide predictions for future experiments in animal models. Understanding the generation of CXCL12 gradients is crucial to inhibiting cancer metastasis.

趋化因子CXCL12（Chemokine CXCL12）可通过C-X-C趋化因子受体4（CXCR4）依赖的机制介导细胞趋化迁移，并已被证实与癌症转移密切相关。尽管目前针对CXCL12梯度的研究多在规整可控的环境中开展，但肿瘤微环境（tumor microenvironment）实则结构紊乱。在活体环境内，CXCL12梯度的形成受多重因素调控：包括分泌与降解CXCL12的细胞数量及排布方式、与细胞外基质（extracellular matrix）的亚型依赖性结合、扩散过程以及昼夜节律波动。本研究构建了肿瘤微环境的计算模型，以模拟紊乱组织内CXCL12梯度的动态变化过程。该模型共得到四项核心发现：其一，相较于CXCL12-α亚型，CXCL12-β与CXCL12-γ亚型可形成强度更高（梯度更陡峭）的CXCL12梯度；其二，表达C-X-C趋化因子受体7（CXCR7）的内皮细胞可通过调控脉管系统附近（而非远处）的CXCL12浓度，调控CXCL12梯度的方向；其三，CXCL12梯度的强度与方向，取决于肿瘤内部分泌型细胞与清道夫型细胞的局部组成；本研究据此提出假说：肿瘤内部存在具备细胞异质性的“微区域”，此类区域可形成朝向血液的强趋化梯度；其四，CXCL12的昼夜节律波动仅影响梯度强度，而非梯度方向。本模型的模拟结果可为未来动物模型相关实验提供理论预测依据。阐明CXCL12梯度的形成机制，对抑制癌症转移具有关键意义。