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

• Published in: Mathematical biosciences 2018-02, Vol.296, p.1-16
• Main Authors: Nargis, Nurun N, Aldredge, Ralph C, Guy, Robert D
• Format: Article
• Language: English
• Subjects: Adhesion; Cancer; Cell proliferation; Chemotaxis; Clinical trials; Computer simulation; Continuum modeling; Cytology; Drug development; Extracellular Matrix; Fragmentation; Fragments; Humans; Invasiveness; Mathematical models; Mathematical morphology; Matrix metalloproteinase; Matrix Metalloproteinases; Medical research; Metalloproteinase; Microenvironments; Mitosis; Models, Theoretical; Morphology; Neoplasms; Nutrients; Proteins; Shrinkage; Simulation; Stability; Tumors
• ISSN: 0025-5564; 1879-3134
• DOI: 10.1016/j.mbs.2017.11.014

•Two-dimensional continuum model for growth and invasion of tumor cells.•Modeling of directed cell motions due to chemotaxis and haptotaxis and the motility-retarding effects of soluble ECM.•Investigation of inhibitory effects of MMP by chemotaxis due to soluble ECM gradient with variation in nutrient availability.•Investigation of the influence of chemotaxis due to soluble-ECM gradients for tumors growing in hypoxic environments.•Important implications on understanding of tumor-invasion processes and development of promising anti-cancer therapeutics. 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 nutri