Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
Cancer Res. 2013 Jul 1;73(13):3833-41. doi: 10.1158/0008-5472.CAN-12-4521. Epub 2013 Apr 30.
The stress harbored by the solid phase of tumors is known as solid stress. Solid stress can be either applied externally by the surrounding normal tissue or induced by the tumor itself due to its growth. Fluid pressure is the isotropic stress exerted by the fluid phase. We recently showed that growth-induced solid stress is on the order of 1.3 to 13.0 kPa (10-100 mmHg)--high enough to cause compression of fragile blood vessels, resulting in poor perfusion and hypoxia. However, the evolution of growth-induced stress with tumor progression and its effect on cancer cell proliferation in vivo is not understood. To this end, we developed a mathematical model for tumor growth that takes into account all three types of stresses: growth-induced stress, externally applied stress, and fluid pressure. First, we conducted in vivo experiments and found that growth-induced stress is related to tumor volume through a biexponential relationship. Then, we incorporated this information into our mathematical model and showed that due to the evolution of growth-induced stress, total solid stress levels are higher in the tumor interior and lower in the periphery. Elevated compressive solid stress in the interior of the tumor is sufficient to cause the collapse of blood vessels and results in a lower growth rate of cancer cells compared with the periphery, independently from that caused by the lack of nutrients due to vessel collapse. Furthermore, solid stress in the periphery of the tumor causes blood vessels in the surrounding normal tissue to deform to elliptical shapes. We present histologic sections of human cancers that show such vessel deformations. Finally, we found that fluid pressure increases with tumor growth due to increased vascular permeability and lymphatic impairment, and is governed by the microvascular pressure. Crucially, fluid pressure does not cause vessel compression of tumor vessels.
肿瘤固相所承受的压力被称为固相压力。固相压力既可以由周围正常组织施加外部压力，也可以由肿瘤自身生长引起。流体压力是由流体相施加的各向同性压力。我们最近发现，生长诱导的固相压力约为 1.3 至 13.0 kPa（10-100mmHg）-足以导致脆弱血管受压，导致灌注不良和缺氧。然而，肿瘤进展过程中生长诱导的压力演变及其对体内癌细胞增殖的影响尚不清楚。为此，我们开发了一种考虑三种类型压力的肿瘤生长数学模型：生长诱导压力、外部施加压力和流体压力。首先，我们进行了体内实验，发现生长诱导的压力与肿瘤体积通过双指数关系相关。然后，我们将此信息纳入我们的数学模型，并表明由于生长诱导的压力的演变，肿瘤内部的总固相压力水平较高，而外围的固相压力水平较低。肿瘤内部升高的压缩固相压力足以导致血管塌陷，与由于血管塌陷导致的营养物质缺乏引起的癌症细胞生长率降低相比，肿瘤内部的癌症细胞生长率降低，而独立于由于血管塌陷导致的营养物质缺乏引起的癌症细胞生长率降低。此外，肿瘤外围的固相压力会导致周围正常组织中的血管变形为椭圆形。我们展示了显示这种血管变形的人类癌症的组织学切片。最后，我们发现由于血管通透性增加和淋巴功能障碍，肿瘤生长导致流体压力增加，并且由微血管压力控制。至关重要的是，流体压力不会导致肿瘤血管的血管压缩。
