The influence of soluble fragments of extracellular matrix (ECM) on tumor growth and morphology

Abstract

A major challenge in matrix-metalloproteinase (MMP) target validation and MMP-inhibitor-drug development for anti-cancer clinical trials is to better understand their complex roles (often competing with each other) in tumor progression. While there is extensive research on the growth-promoting effects of MMPs, the growth-inhibiting effects of MMPs has not been investigated thoroughly. So we develop a continuum model of tumor growth and invasion including chemotaxis and haptotaxis in order to examine the complex interaction between the tumor and its host microenvironment and to explore the inhibiting influence of the gradients of soluble fragments of extracellular matrix (ECM) density on tumor growth and morphology. Previously, it was shown both computationally (in one spatial dimension) and experimentally that the chemotactic pull due to soluble ECM gradients is anti-invasive, contrary to the traditional view of the role of chemotaxis in malignant invasion [1]. With two-dimensional numerical simulation and using a level set based tumor-host interface capturing method, we examine the effects of chemotaxis on the progression and morphology of a tumor growing in nutrient-rich and nutrient-poor microenvironments which was not investigated before. In particular we examine how the geometry of the growing tumor is affected when placed in different environments. We also investigate the effects of varying ECM degradation rate, the production rate of matrix degrading enzymes (MDE), and the conversion of ECM into soluble ECM. We find that chemotaxis due to ECM-fragment gradients strongly influences tumor growth and morphology, and that the instabilities caused by tumor cell proliferation and haptotactic movements can be prevented if chemotaxis is sufficiently strong. The influence of chemotaxis and the above factors on tumor growth and morphology are found to be more prominent in nutrient-poor environments than in nutrientrich environments. So we extend our investigations of these antinvasive chemotactic influences by examining the effects of cell-cell and cell-ECM adhesion and low proliferation rate for tumors growing in low-nutrient environments. We find that as the extent of chemotaxis increases, the effects of adhesion on tumor growth and shape become negligible. Under conditions of low cell mitosis, chemotaxis may cause the tumor to shrink, as the extent of chemotaxis increases. Both stable and unstable tumor shrinkage are predicted by our model. Unexpectedly, in some cases chemotaxis may contribute toward developing instability where haptotaxis alone induces stable growth.

Integrated cancer tissue engineering models for precision medicine

“…Meanwhile, cellular interactions between the non-malignant cell populations, immune components[11,12], and cancer cells influence the advancement of the disease, as well as, the response to common treatments[13]. Additionally, acellular aspects of the microenvironment, including soluble signaling and ECM composition and architecture, play a large role in phenotypic behavior[14,15] and thus the conclusions of experimental outcomes. Each of these factors uniquely impacts cellular components within the tumor microenvironment (TME), contributing to the complexity of the ‘cancer-organ’ system (Fig 1).…”

Novel mechanisms and biomarkers in alcohol-induced organ injury.

“…the 'degradome') in various diseases are becoming increasingly understood. For example, ECM degradation rate, the production rate of matrix degrading enzymes (MDE), and the conversion of ECM into soluble ECM have been demonstrated to strongly influence tumor growth and morphology (56).…”