Modeling Physical Forces Experienced by Cancer and Stromal Cells Within Different Organ-Specific Tumor Tissue

Abstract

Mechanical force exerted on cancer cells by their microenvironment have been reported to drive cells toward invasive phenotypes by altering cells' motility, proliferation, and apoptosis. These mechanical forces include compressive, tensile, hydrostatic, and shear forces. The importance of forces is then hypothesized to be an alteration of cancer cells' and their microenvironment's biophysical properties as the indicator of a tumor's malignancy state. Our objective is to investigate and quantify the correlation between a tumor's malignancy state and forces experienced by the cancer cells and components of the microenvironment. In this study, we have developed a multicomponent, three-dimensional model of tumor tissue consisting of a cancer cell surrounded by fibroblasts and extracellular matrix (ECM). Our results on three different organs including breast, kidney, and pancreas show that: A) the stresses within tumor tissue are impacted by the organ specific ECM's biophysical properties, B) more invasive cancer cells experience higher stresses, C) in pancreas which has a softer ECM (Young modulus of 1.0 kPa) and stiffer cancer cells (Young modulus of 2.4 kPa and 1.7 kPa) than breast and kidney, cancer cells experienced significantly higher stresses, D) cancer cells in contact with ECM experienced higher stresses compared to cells surrounded by fibroblasts but the area of tumor stroma experiencing high stresses has a maximum length of 40 μm when the cancer cell is surrounded by fibroblasts and 12 μm for when the cancer cell is in vicinity of ECM. This study serves as an important first step in understanding of how the stresses experienced by cancer cells, fibroblasts, and ECM are associated with malignancy states of cancer cells in different organs. The quantification of forces exerted on cancer cells by different organ-specific ECM and at different stages of malignancy will help, first to develop theranostic strategies, second to predict accurately which tumors will become highly malignant, and third to establish accurate criteria controlling the progression of cancer cells malignancy. Furthermore, our in silico model of tumor tissue can yield critical, useful information for guiding ex vivo or in vitro experiments, narrowing down variables to be investigated, understanding what factors could be impacting cancer treatments or even biomarkers to be looking for.

Keywords: Cancer cells; ECM; cell mechanics; fibroblasts; forces on cells; malignancy; tumor microenvironment.

FIGURE 1.

A) Schematic representation of a tumor tissue and its components. B) Three-dimensional model of the tumor microenvironment when a cancer cell is in contact the surrounding fibroblasts, C) when a cancer cell is in contact with the ECM.

FIGURE 2.

The von Mises stress distribution within tumor tissue when the cancer cells is surrounded by fibroblasts and when the cancer cell is in vicinity of ECM. Results are shown for breast cancer cell lines, MCF-7 and T47D, the kidney cancer cell lines, ACHN and A-498, and the pancreatic cancer cell lines, PANC-1 and MIA PaCa-2. Figures 2A, 2B, 2C, 2F, 2G, and 2H show the stresses along the tissue width (x-axis); Figures 2D and 2I demonstrate the stresses along the tissue length (y-axis); Figures 2E and 2J show the stresses along the tissue thickness (z-axis). Note that a boundary load of 10 mmHg (1,333 Pa) is applied

FIGURE 3.

The von Mises stress distribution within tumor tissue when the cancer cells is surrounded by fibroblasts and when the cancer cell is in vicinity of ECM. Results are shown for breast cancer cell lines, MCF-7 and T47D, the kidney cancer cell lines, ACHN and A-498, and the pancreatic cancer cell lines, PANC-1 and MIA PaCa-2. Figures 3A, 3B, 3C, 3F, 3H, and 3G show the stresses along the tissue width (x-axis); Figures 3D and 3I demonstrate the stresses along the tissue length (y-axis); Figures 3E and 3J show the stresses along the tissue thickness (z-axis). Note that a boundary load of 20 mmHg (2,666 Pa) is applied.

FIGURE 4.

The von Mises stress distribution across the tumor stroma with boundary load of 10 mmHg for A) breast tissue with MCF-7, B) breast tissue and T47D, C) kidney tissue with ACHN, D) kidney tissue with A-498 ECM, E) pancreas tissue with PANC-1, F) pancreas tissue with MIA-PaCa-2.

FIGURE 5.

The averaged von Mises stress values over whole tumor tissue. Note that “inside” here means the cancer cell is in contact with the surrounding fibroblasts and “outside” means that the cancer cell is in contact with the ECM.