The role of mechanical forces in tumor growth and therapy

Abstract

Tumors generate physical forces during growth and progression. These physical forces are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. When exerted directly on cancer cells, they can increase cells' invasive and metastatic potential. Tumor vessels-while nourishing the tumor-are usually leaky and tortuous, which further decreases perfusion. Hypoperfusion and hypoxia contribute to immune evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies, including radiation. In parallel, vessel leakiness together with vessel compression causes a uniformly elevated interstitial fluid pressure that hinders delivery of blood-borne therapeutic agents, lowering the efficacy of chemo- and nanotherapies. In addition, shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells. Taming these physical forces can improve therapeutic outcomes in many cancers.

Keywords: solid stress; stress alleviation; tumor microenvironment; tumor perfusion; vascular hyperpermeability; vascular normalization; vessel compression.

Figure 1

Schematic of the tumor mechanical microenvironment. Cancer cells along with myfibroblasts (stromal cells) stretch collagen fibers and compress hyaluronan storing growth-induced solid stress. This stress can compress or even collapse intratumoral vessels reducing blood flow. The remaining uncompressed vessels are often leaky resulting in excessive fluid crossing the vessel wall and contributing to elevated interstitial fluid pressure. Vessel leakiness further reduces perfusion and along with vessel compression can cause blood stasis. At the macroscopic scale the tumor pushes against the surrounding normal tissue, which in turn restricts tumor expansion.

Figure 2

Solid stress profile in tumors and evidence of vessel compression. A | Solid stresses are compressive in the interior of the tumor in both radial and circumferential direction, while at the periphery radial stresses are compressive and circumferential stresses are tensile. [Reproduced from Reference (3)]. B | This stress profile can collapse intratumor vessels (histologic section of human pancreatic tumor [Reproduced from Reference (135)], arrows show position of collapsed vessels), while peripheral vessels obtain elliptical shapes (histologic section of human pancreatic neuroendocrine tumor [Reproduced from Reference (3)], dash lines show tumor margin and the two main axes of the arterioles). Scale bar 100 μm.

Figure 3

External and growth induced stress. A | Direct cancer cell compression enhances the invasive phenotype of 67NR cells. 67NR monolayers form a rosette shape, the control group is stress-free, while the compressed group is subject to 773 Pa compressive stress. Under compressive stress the 67NR cells move faster towards the center of the rosette, which suggests increased motility and invasiveness. Scale bar 100 μm [Reproduced from Reference (10)]. B | Evidence of growth-induced stress. Cutting of an excised tumor along its longest axis (80% of its thickness) causes retraction of the surface and swelling of the interior of the tumor. These deformation modes are caused by relaxation of the growth-induced stress and result in a measurable tumor opening. Thus, even though no external loads are exerted on the excised tumor, the tumor still holds growth-induced, residual stress. Growth-induced stress is estimated with the use of mathematical modeling by simulating the cutting experiment [Reproduced from Reference (2)]. The tumor in the figure is a soft tissue sarcoma.

Figure 4

Abnormal fluid flow in tumors. A | Red blood cell (RBC) flux and blood velocity in interior and peripheral vessels of a glioma growing in a mouse brain. A significantly larger proportion of interior vessels are hypo-perfused with velocities less than 0.1 mm/s compared to peripheral vessels [Reproduced from Reference (47)]. B | Interstitial fluid pressure in tumors is elevated and comparable to microvascular pressure [Reproduced from Reference (108)]. C | Lymphatics are absent from the tumor interior and hyperplastic at the periphery. Fluorescence lymphangiography images of a normal (top) and a sarcoma-bearing (bottom) mouse tail. At the normal tissue, lymphatics form a functional network (green). At the tumor interior (right side of bottom panel) lymphatics are absent, but have a larger diameter at the margin. Large arrows indicate attenuated vessels inside the tumor. Small arrows indicate the increased diameter of the lymphatic capillary at the margin [Reproduced from Reference (91)]).

Figure 5

Strategies to improve perfusion and drug delivery in solid tumors. (A) Vascular normalization increases pericyte coverage, which decreases vessel permeability and improves perfusion, (B) Stress-alleviation treatment depletes structural components of the tumor microenvironment, which decompresses tumor vessels and improves perfusion [Reproduced from Reference (15)]. Improved perfusion rates will increase the delivery of drugs. These strategies can be used either alone or in combination based on whether tumor vessels are leaky, compressed, both or none. Abbreviations EC: endothelial cell, BM: basement membrane, PC: pericyte, CC: cancer cell, ECM: extracellular matrix.

Figure 6

Stress alleviation treatment. A | Intravital multiphoton microscopy images show treatment with the angiotensin receptor blocker, losartan lowers collagen levels (blue) and increases the density of perfused vessels (green) in an orthotopic mammary adenocarcinoma (EO771) [Reproduced from Reference (135)]. Treatment with the sonic hedgehog inhibitor Saridegib, B | reduces solid stress levels, measured as a function of tumor opening (Fig. 3), in two pancreatic ductal adenocarcinomas (AK4.4 and Capan2), C | increases blood and lymphatic vessel diameter and D | the fraction of perfused vessels, E | without affecting vascular density [Panels B-E reproduced from Reference (135)] (2). Scale bar 1 mm. Asterisks represent a statistically significant deference (P < 0.05).

Figure 7

Vascular normalization treatment with the monoclonal antibody DC101. Normalization of tumor vessels improve tumor perfusion in a dose-dependent manner. A | Perfusion images of whole tumor tissue taken by multispectral confocal microscopy. Animals treated with IgG (control) and 10, 20, or 40 mg/kg bw DC101. Green, Sytox staining. (Scale bars, 1,000 μm.). B | Quantification of fractions of Hoechst 33342-positive area in whole tumor area show perfused regions in the tumors for the three DC101 doses (*P < 0.05) [Panels A adapted from and panel B reproduced from Reference (145)]. C | Model predictions for the effect of vessel wall pore size on the pressure difference across the tumor vessel wall. Decrease in vessel wall pore size with vascular normalization restores a transvascular pressure difference [Reproduced from Reference (23)]. D | Normalization of tumor vasculature and the resulting increase in transvascular pressure difference, improves flux of nanoparticles across the tumor vessel wall in a size-dependent manner in orthotopic mammary adenocarcinomas (EO771 and 4T1) [Reproduced from Reference (23)].