Department of Mathematics, University of California, Irvine, USA.
J Theor Biol. 2013 Mar 7;320:131-51. doi: 10.1016/j.jtbi.2012.11.031. Epub 2012 Dec 7.
The flow of interstitial fluid and the associated interstitial fluid pressure (IFP) in solid tumors and surrounding host tissues have been identified as critical elements in cancer growth and vascularization. Both experimental and theoretical studies have shown that tumors may present elevated IFP, which can be a formidable physical barrier for delivery of cell nutrients and small molecules into the tumor. Elevated IFP may also exacerbate gradients of biochemical signals such as angiogenic factors released by tumors into the surrounding tissues. These studies have helped to understand both biochemical signaling and treatment prognosis. Building upon previous work, here we develop a vascular tumor growth model by coupling a continuous growth model with a discrete angiogenesis model. We include fluid/oxygen extravasation as well as a continuous lymphatic field, and study the micro-environmental fluid dynamics and their effect on tumor growth by accounting for blood flow, transcapillary fluid flux, interstitial fluid flow, and lymphatic drainage. We thus elucidate further the non-trivial relationship between the key elements contributing to the effects of interstitial pressure in solid tumors. In particular, we study the effect of IFP on oxygen extravasation and show that small blood/lymphatic vessel resistance and collapse may contribute to lower transcapillary fluid/oxygen flux, thus decreasing the rate of tumor growth. We also investigate the effect of tumor vascular pathologies, including elevated vascular and interstitial hydraulic conductivities inside the tumor as well as diminished osmotic pressure differences, on the fluid flow across the tumor capillary bed, the lymphatic drainage, and the IFP. Our results reveal that elevated interstitial hydraulic conductivity together with poor lymphatic function is the root cause of the development of plateau profiles of the IFP in the tumor, which have been observed in experiments, and contributes to a more uniform distribution of oxygen, solid tumor pressure and a broad-based collapse of the tumor lymphatics. We also find that the rate that IFF is fluxed into the lymphatics and host tissue is largely controlled by an elevated vascular hydraulic conductivity in the tumor. We discuss the implications of these results on microenvironmental transport barriers, and the tumor invasive and metastatic potential. Our results suggest the possibility of developing strategies of targeting tumor cells based on the cues in the interstitial fluid.
间质液的流动及其相关的间质液压力（IFP）在实体瘤和周围宿主组织中已被确定为癌症生长和血管生成的关键因素。实验和理论研究均表明，肿瘤可能会表现出升高的 IFP，这可能是细胞营养物质和小分子进入肿瘤的强大物理屏障。升高的 IFP 也可能加剧肿瘤释放到周围组织中的生化信号（如血管生成因子）的浓度梯度。这些研究有助于理解生化信号和治疗预后。在此基础上，我们通过将连续生长模型与离散血管生成模型耦合，开发了一种血管肿瘤生长模型。我们包括流体/氧气渗出以及连续的淋巴管场，并通过考虑血流、跨毛细血管流体通量、间质液流和淋巴引流来研究微环境流体动力学及其对肿瘤生长的影响。因此，我们进一步阐明了导致实体瘤中间质压力影响的关键因素之间的复杂关系。特别是，我们研究了 IFP 对氧气渗出的影响，结果表明小的血管/淋巴管阻力和塌陷可能导致跨毛细血管流体/氧气通量降低，从而降低肿瘤生长速度。我们还研究了肿瘤血管病变对肿瘤毛细血管床的流体流动、淋巴引流和 IFP 的影响，包括肿瘤内血管和间质水力传导率升高以及渗透压差降低。我们的结果表明，升高的间质水力传导率加上较差的淋巴功能是导致肿瘤中 IFP 平台轮廓发展的根本原因，这在实验中已经观察到，并有助于氧气、实体瘤压力更均匀的分布和肿瘤淋巴管的广泛塌陷。我们还发现，IFP 流入淋巴管和宿主组织的速率主要受肿瘤中血管水力传导率升高的控制。我们讨论了这些结果对微环境传输障碍以及肿瘤侵袭和转移潜力的影响。我们的结果表明，基于间质液中的线索，靶向肿瘤细胞的策略是有可能的。
