Solving the Puzzle of Metastasis: The Evolution of Cell Migration in Neoplasms

Genomics and Computational Biology Program, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS ONE (Impact Factor: 3.23). 04/2011; 6(4):e17933. DOI: 10.1371/journal.pone.0017933
Source: PubMed


Metastasis represents one of the most clinically important transitions in neoplastic progression. The evolution of metastasis is a puzzle because a metastatic clone is at a disadvantage in competition for space and resources with non-metastatic clones in the primary tumor. Metastatic clones waste some of their reproductive potential on emigrating cells with little chance of establishing metastases. We suggest that resource heterogeneity within primary tumors selects for cell migration, and that cell emigration is a by-product of that selection.
We developed an agent-based model to simulate the evolution of neoplastic cell migration. We simulated the essential dynamics of neoangiogenesis and blood vessel occlusion that lead to resource heterogeneity in neoplasms. We observed the probability and speed of cell migration that evolves with changes in parameters that control the degree of spatial and temporal resource heterogeneity. Across a broad range of realistic parameter values, increasing degrees of spatial and temporal heterogeneity select for the evolution of increased cell migration and emigration.
We showed that variability in resources within a neoplasm (e.g. oxygen and nutrients provided by angiogenesis) is sufficient to select for cells with high motility. These cells are also more likely to emigrate from the tumor, which is the first step in metastasis and the key to the puzzle of metastasis. Thus, we have identified a novel potential solution to the puzzle of metastasis.

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Available from: Carlo Maley, Mar 24, 2015
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    • "Others use mathematical models of cell growth and specific biologic processes such as matrix modeling and migration to predict metastasis growth over time [77-80]. Agent-based modeling of metastases has been employed to characterize the selective forces involved in the generation of circulating, potentially metastatic tumor cells [81,82], implicate the role of host immunity in the generation of satellite metastases [1,2,4,10-14], and examine the interactions of metastatic tumor cells with the host immune system for optimizing tumor vaccine delivery [15-18]. Other models of individual tumor cell interactions with host environment, employing knowledge of biomechanics and enzyme kinetics in a system of differential equations that describe integrin interactions and tumor cell growth patterns [83,84]. "
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    ABSTRACT: Metastatic tumors are a major source of morbidity and mortality for most cancers. Interaction of circulating tumor cells with endothelium, platelets and neutrophils play an important role in the early stages of metastasis formation. These complex dynamics have proven difficult to study in experimental models. Prior computational models of metastases have focused on tumor cell growth in a host environment, or prediction of metastasis formation from clinical data. We used agent-based modeling (ABM) to dynamically represent hypotheses of essential steps involved in circulating tumor cell adhesion and interaction with other circulating cells, examine their functional constraints, and predict effects of inhibiting specific mechanisms. We developed an ABM of Early Metastasis (ABMEM), a descriptive semi-mechanistic model that replicates experimentally observed behaviors of populations of circulating tumor cells, neutrophils, platelets and endothelial cells while incorporating representations of known surface receptor, autocrine and paracrine interactions. Essential downstream cellular processes were incorporated to simulate activation in response to stimuli, and calibrated with experimental data. The ABMEM was used to idenpngy potential points of interdiction through examination of dynamic outcomes such as rate of tumor cell binding after inhibition of specific platelet or tumor receptors. The ABMEM reproduced experimental data concerning neutrophil rolling over endothelial cells, inflammation-induced binding between neutrophils and platelets, and tumor cell interactions with these cells. Simulated platelet inhibition with anti-platelet drugs produced unstable aggregates with frequent detachment and re-binding. The ABMEM replicates findings from experimental models of circulating tumor cell adhesion, and suggests platelets play a critical role in this pre-requisite for metastasis formation. Similar effects were observed with inhibition of tumor integrin alphaV/beta3. These findings suggest that anti-platelet or anti-integrin therapies may decrease metastasis by preventing stable circulating tumor cell adhesion. Circulating tumor cell adhesion is a complex, dynamic process involving multiple cell-cell interactions. The ABMEM successfully captures the essential interactions necessary for this process, and allows for in-silico iterative characterization and invalidation of proposed hypotheses regarding this process in conjunction with in-vitro and in-vivo models. Our results suggest that anti-platelet therapies and anti-integrin therapies may play a promising role in inhibiting metastasis formation.
    Theoretical Biology and Medical Modelling 04/2014; 11(1):17. DOI:10.1186/1742-4682-11-17 · 0.95 Impact Factor
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    • "This is exemplified by the fact that not only tumor growth, invasiveness , and metastasis were influenced by resource availability , the former were also shown to be greatly affected by the spatial arrangement of noncancerous cells and macromolecules in the tumor microenvironment (Anderson et al. 2006; Lee et al. 2011). A heterogeneous spatial arrangement drives selection toward a few dominant clones, with a high propensity to emigrate from the tumor (metastasis), with invasive (fingering margins) tumor morphology , whereas homogeneous spatial arrangements allow for the coexistence of many phenotypes, more or less aggressive, with noninvasive (smooth margins) tumor morphology (Anderson et al. 2006; Chen et al. 2011; Lee et al. 2011). Here, we explore and offer new insights into the spatial aspects of tumor–microenvironment interactions by comparing landscape ecology theory with tumor growth and metastasis within the tissue microhabitat, an approach that has already successfully applied to health problems such as antibiotic resistances in wildlife (Singer et al. 2006). "
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    ABSTRACT: Cancer is now understood to be a process that follows Darwinian evolution. Heterogeneous populations of cancerous cells that make up the tumor inhabit the tissue 'microenvironment', where ecological interactions analogous to predation and competition for resources drive the somatic evolution of cancer. The tumor microenvironment plays a crucial role in the tumor genesis, development, and metastasis processes, as it creates the microenvironmental selection forces that ultimately determine the cellular characteristics that result in the greatest fitness. Here, we explore and offer new insights into the spatial aspects of tumor-microenvironment interactions through the application of landscape ecology theory to tumor growth and metastasis within the tissue microhabitat. We argue that small tissue microhabitats in combination with the spatial distribution of resources within these habitats could be important selective forces driving tumor invasiveness. We also contend that the compositional and configurational heterogeneity of components in the tissue microhabitat do not only influence resource availability and functional connectivity but also play a crucial role in facilitating metastasis and may serve to explain, at least in part, tissue tropism in certain cancers. This novel work provides a compelling argument for the necessity of taking into account the structure of the tissue microhabitat when investigating tumor progression.
    Evolutionary Applications 01/2013; 6(1):82-91. DOI:10.1111/eva.12031 · 3.90 Impact Factor
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    • "In effect, prior to metastases, most cancers can be cured surgically and 5-year survival rates are about 90%. However, when a tumor has spread to different sites, those rates, even using some forms of systemic therapy (for example, chemotherapy), often fall below 15% [21]. Taking into account that the growth of tumor cells re-inoculated into animals bearing a primary tumor mimics the situation that is observed during metastases formation, the understanding of the mechanisms underlying the phenomenon of CR may help to understand the mechanisms responsible for the growth-inhibition of metastatic cells in the presence of a primary tumor. "
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    ABSTRACT: Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants. This phenomenon has been described in human and animal systems and it can be generated by both immunogenic and non-immunogenic tumors. The relevance of CR to the mechanisms of metastases control has been highlighted by numerous observations showing that the removal of human and murine tumors may be followed by an abrupt increase in metastatic growth, suggesting that a primary tumor may exert a controlling action on its metastases which could be considered as secondary tumor implants developed spontaneously during the primary tumor growth. A more profound understanding of the different mechanisms claimed to be associated with the phenomenon of CR could contribute to develop new and more harmless means to manage malignant diseases, especially by limiting the development of metastases that arise after resection of primary tumors or after other stressors that may promote the escape of metastases from dormancy.
    Cancer letters 05/2012; 324(2):133-41. DOI:10.1016/j.canlet.2012.05.021 · 5.62 Impact Factor
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