Stress-mediated progression of solid tumors: effect of mechanical stress on tissue oxygenation, cancer cell proliferation, and drug delivery

Abstract

Oxygen supply plays a central role in cancer cell proliferation. While vascular density increases at the early stages of carcinogenesis, mechanical solid stresses developed during growth compress tumor blood vessels and, thus, drastically reduce the supply of oxygen, but also the delivery of drugs at inner tumor regions. Among other effects, hypoxia and reduced drug delivery compromise the efficacy of radiation and chemo/nano therapy, respectively. In the present study, we developed a mathematical model of tumor growth to investigate the interconnections among tumor oxygenation that supports cancer cell proliferation, the heterogeneous accumulation of mechanical stresses owing to tumor growth, the non-uniform compression of intratumoral blood vessels due to the mechanical stresses, and the insufficient delivery of oxygen and therapeutic agents because of vessel compression. We found that the high vascular density and increased cancer cell proliferation often observed in the periphery compared to the interior of a tumor can be attributed to heterogeneous solid stress accumulation. Highly vascularized peripheral regions are also associated with greater oxygenation compared with the compressed, less vascularized inner regions. We also modeled the delivery of drugs of two distinct sizes, namely chemotherapy and nanomedicine. Model predictions suggest that drug delivery is affected negatively by vessel compression independently of the size of the therapeutic agent. Finally, we demonstrated the applicability of our model to actual geometries, employing a breast tumor model derived from MR images.

Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity

“…Hyaluronan and other glycosaminoglycans in the matrix or glycocalyx (Paszek et al 2014) resist intratumor radial and circumferential compression, which is a result of resistance to peripheral, circumferential tensile stress by collagen fibers (Chauhan et al 2013; Stylianopoulos et al 2013; Pirentis et al 2015). Thus, the mechanical properties of the ECM contribute to heterogeneous solid stress distribution, thereby dictating the morphology of compressed vessels and oxygen concentrations (Stylianopoulos et al 2013; Mpekris et al 2015). …”

Hyaluronan-Derived Swelling of Solid Tumors, the Contribution of Collagen and Cancer Cells, and Implications for Cancer Therapy

“…Based on our previous work [1], [29], [30], [37], [38], a mathematical model was developed and informed by our experimental data to calculate the Donnan osmotic pressure and the solid stress exerted by the host tissue on the tumor, which cannot be measured experimentally. The model consisted of three phases: the solid and fluid phase and the ions (positive and negative).…”

“…The model consisted of three phases: the solid and fluid phase and the ions (positive and negative). Furthermore, it employed the multiplicative decomposition of the deformation gradient tensor to model tumor growth, accounting also for the effect tumor oxygenation and solid stress on cancer cell proliferation [38], [39], [40]. A detailed description of the mathematical model is given in the Supplementary Material.…”

Evaluating the influence of mechanical stress on anticancer treatments through a multiphase porous media model

“…In particular, the first papers addressing the modeling of contact inhibition effects were (Chaplain et al, 2006; Galle et al, 2009). Some models describe the action of a therapeutic agent on tumor spheroids (see for example (Frieboes et al, 2009; Goodman et al, 2008; Ward and King, 2003)), whereas others take into account in vivo settings, as in (Hossain et al, 2012; Kim et al, 2013; Mpekris et al, 2015). There are also models addressing the effects of mechanical stress on tumor development, such as those in (Kim et al, 2011; Loessner et al, 2013; Stylianopoulos et al, 2012).…”