Collective behavior of brain tumor cells: The role of hypoxia

Khain, Evgeniy; Katakowski, Mark; Hopkins, Scott; Szalad, Alexandra; Zheng, Xuguang; Jiang, Feng; Chopp, Michael

doi:10.1103/physreve.83.031920

Cited by 68 publications

(104 citation statements)

References 47 publications

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“…Why would a metastatic cell activate an anaerobic metabolic pathway and bypass the mitochondria? One answer seems to be that the interior of a cancer tumor is very acidic and hypoxic (7)(8)(9). In this highly stressful anaerobic microenvironment, fitness is conferred by the Warburg cycle despite its low thermodynamic efficiency.…”

mentioning

confidence: 99%

Minimization of thermodynamic costs in cancer cell invasion

Liu

Duclos

Sun³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Metastasis, the truly lethal aspect of cancer, occurs when metastatic cancer cells in a tumor break through the basement membrane and penetrate the extracellular matrix. We show that MDA-MB-231 metastatic breast cancer cells cooperatively invade a 3D collagen matrix while following a glucose gradient. The invasion front of the cells is a dynamic one, with different cells assuming the lead on a time scale of 70 h. The front cell leadership is dynamic presumably because of metabolic costs associated with a long-range strain field that precedes the invading cell front, which we have imaged using confocal imaging and marker beads imbedded in the collagen matrix. We suggest this could be a quantitative assay for an invasive phenotype tracking a glucose gradient and show that the invading cells act in a cooperative manner by exchanging leaders in the invading front.T umor metastasis is obviously of enormous clinical importance.A fundamental physiologic and clinical difference between benign and malignant tumor cells is that the former are usually neither invasive nor fatal. It is currently difficult to predict the probability of metastasis from the morphological or phenotypic properties of tumor cells observed within a primary cancer. Invasive tumor growth, at both primary and secondary sites, requires tumor cells to break through the stromal tissue barrier, evade the immune system, and coordinate signaling among tumor and mesenchymal cells to promote formation of tissue infrastructure, such as angiogenesis, to maintain tumor viability in its newly invaded space (1). We test two hypotheses: (i) The extreme thermodynamic costs of the oxidative Warburg cycle used by cancer cells forces them to follow glucose gradients; and (ii) minimization of the thermodynamic costs can be achieved by collective invasion strategies.Invading cells are subject to significant potential fitness costs that may be minimized by collective behavior. Metastatic tumor cells that leave the primary tumor have to break through the stromal tissue barrier, evade the immune system, and coordinate with other local cells during angiogenesis to finally set up a viable remote tumor. It has been estimated that less than 1% of the primary tumor cells are able to finish the metastasis cycle (2), and yet they contribute to more than 90% of the cancer-related deaths (3). Although the molecular details are still unclear, it is significant that the malignant transition is accompanied by a change in the metabolism pathway from the mitochondrial oxidation of pyruvate in mitochondria (an aerobic process) to the far less energy-efficient and ancient anaerobic pathway of glycolysis followed by lactic acid fermentation in the cytosol (4), known as the Warburg cycle (5).Most, if not all, metastatic cancer cells use the Warburg cycle, which is a far less efficient metabolism in terms of ATP production (6), consuming glucose (glycolysis) rather than using the usual oxidative Krebs phosphorylation cycle, although, thermodynamically, the process is efficient in the storage...

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mentioning

confidence: 99%

Minimization of thermodynamic costs in cancer cell invasion

Liu

Duclos

Sun³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Previously, we demonstrated that hypoxia contributes to glioma migration by decreasing cell-to-cell adhesion rather than increasing individual cell motility [25]. It was recently reported that hypoxia promotes hypoxia inducible factor 1α (HIF-1α) -mediated up-regulation of miR-9 in pulmonary artery smooth muscle cells, however the effect of hypoxia upon miR-9 in tumor has yet to be investigated [11].…”

Section: Resultsmentioning

confidence: 99%

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

Katakowski

Charteris

Chopp

et al. 2016

Cancer Microenvironment

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The phenotypic axis of invasion and proliferation in malignant glioma cells is a well-documented phenomenon. Invasive glioma cells exhibit a decreased proliferation rate and a resistance to apoptosis, and invasive tumor cells dispersed in brain subsequently revert to proliferation and contribute to secondary tumor formation. One miRNA can affect dozens of mRNAs, and some miRNAs are potent oncogenes. Multiple miRNAs are implicated in glioma malignancy, and several of which have been identified to regulate tumor cell motility and division. Using rat 9 L gliosarcoma and human U87 glioblastoma cell lines, we investigated miRNAs associated with the switch between glioma cell invasion and proliferation. Using micro-dissection of 9 L glioma tumor xenografts in rat brain, we identified disparate expression of miR-9 between cells within the periphery of the primary tumor, and those comprising tumor islets within the invasive zone. Modifying miR-9 expression in in vitro assays, we report that miR-9 controls the axis of glioma cell invasion/proliferation, and that its contribution to invasion or proliferation is biphasic and dependent upon local tumor cell density. In addition, immunohistochemistry revealed elevated hypoxia inducible factor 1 alpha (HIF-1α) in the invasive zone as compared to the primary tumor periphery. We also found that hypoxia promotes miR-9 expression in glioma cells. Based upon these findings, we propose a hypothesis for the contribution of miR-9 to the dynamics glioma invasion and satellite tumor formation in brain adjacent to tumor.

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“…The periodic boundary conditions were used along the vertical direction, whereas open boundaries were used for the horizontal direction, which represents the direction of tumor invasion. Our approach is similar to the scenario when Bindsschadler and McGrath [67] and Khain et al [68] used parallel strips surrounded by cell-cultured strips made with microfabricated stencils for observation of collective cell migration. For the sake of simplification, we assumed that an initial tumor seed is located at x' = 0 and y' = 0.5 and spreads isotropically.…”

Section: Model With Nondimensionalization and Parameterizationmentioning

confidence: 86%

Tumor proliferation and diffusion on percolation clusters

et al. 2016

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We study in silico the influence of host tissue inhomogeneity on tumor cell proliferation and diffusion by simulating the mobility of a tumor on percolation clusters with different homogeneities of surrounding tissues. The proliferation and diffusion of a tumor in an inhomogeneous tissue could be characterized in the framework of the percolation theory, which displays similar thresholds (0.54, 0.44, and 0.37, respectively) for tumor proliferation and diffusion in three kinds of lattices with 4, 6, and 8 connecting near neighbors. Our study reveals the existence of a critical transition concerning the survival and diffusion of tumor cells with leaping metastatic diffusion movement in the host tissues. Tumor cells usually flow in the direction of greater pressure variation during their diffusing and infiltrating to a further location in the host tissue. Some specific sites suitable for tumor invasion were observed on the percolation cluster and around these specific sites a tumor can develop into scattered tumors linked by some advantage tunnels that facilitate tumor invasion. We also investigate the manner that tissue inhomogeneity surrounding a tumor may influence the velocity of tumor diffusion and invasion. Our simulation suggested that invasion of a tumor is controlled by the homogeneity of the tumor microenvironment, which is basically consistent with the experimental report by Riching et al. as well as our clinical observation of medical imaging. Both simulation and clinical observation proved that tumor diffusion and invasion into the surrounding host tissue is positively correlated with the homogeneity of the tissue.

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Collective behavior of brain tumor cells: The role of hypoxia

Cited by 68 publications

References 47 publications

Minimization of thermodynamic costs in cancer cell invasion

Minimization of thermodynamic costs in cancer cell invasion

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

Tumor proliferation and diffusion on percolation clusters

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