The effect of interstitial pressure on tumor growth: Coupling with the blood and lymphatic vascular systems

Abstract

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.

Towards a unified approach in the modeling of fibrosis: A review with research perspectives

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Effects of Matrix Metalloproteinase on Tumour Growth and Morphology via Haptotaxis

“…In a continuum model, the cell species velocity is obtained from the inertia less momentum conservation equation based on Darcy's law, representing the instantaneous equilibrium among forces associated with pressure, cell adhesion, elastic forces, forces exchanged with the ECM leading to haptotaxis and chemo taxis due to gradients of nutrient and other growth factors, and other mechanical effects. The continuum models incorporate the adhesion among cancer cells by a surface tension at the tumour surface [20][21][22]24,37,41,[43][44][45][46][47][48][49][50]. Surface tension also models cell-ECM adhesion and the presence of a membrane, or capsule, formed of ECM macromolecules that may encapsulate tumours in vitro and in vivo.…”

Tumor Interstitial Fluid Promotes Malignant Phenotypes of Lung Cancer Independently of Angiogenesis

“…8). Both experimental and theoretical studies have shown that IFP is elevated in the tumors of patients with cancer, and whereas little TIF is found in the tumor interior, it is primarily present near the tumor boundary (9).…”