Probing the invasiveness of prostate cancer cells in a 3D microfabricated landscape

Liu, Liyu; Sun, Bo; Pedersen, Jonas Nyvold; Yong, Koh Meng Aw; Getzenberg, Robert H.; Stone, Howard A.; Austin, Robert H.

doi:10.1073/pnas.1102808108

Cited by 37 publications

(46 citation statements)

References 26 publications

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“…In the 2D wound-healing experiment, the cancer cells appeared to expand outward into the soft matrix, basically as a free gas of cells, which is consistent with the idea that cancer cells do not obey contact inhibition (34,48,49). However, for the 3D metastatic invading front, it would appear that there are correlations between the invading cells on the front because it remains a fairly tightly focused front and does not disperse.…”

Section: Discussionsupporting

confidence: 68%

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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Section: Discussionsupporting

confidence: 68%

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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“…Interestingly, each Tepui top is either devoid or occupied by LNCaP cells, whereas PC-3 cells occupy all Tepui tops. These observations are consistent with contact inhibition (2).…”

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confidence: 82%

“…As expected, LNCaP cells show a lower invasion rate (i.e., longer time to reach the top of the Tepuis) than PC-3 cells (2). Less expected is the observed lower invasion efficiency of LNCaP cells compared with PC-3 cells (2) (i.e., a lower percentage of Tepui tops are occupied by LNCaP cells at steady state); 15% Tepui tops remain unoccupied by less-invasive LNCaP cells.…”

mentioning

confidence: 78%

“…Therefore, it would be interesting to determine whether traditional wound-healing assays, where a cell monolayer is wounded and rates of closure of the newly created empty space are recorded, lead to the same differential invasion efficiency as the Tepuis assay. It could also be informative to make use of microlithography to generate a flattened, 2D version of the 3D Tepuis by Liu et al (2). This 2D version of the assay by Liu et al (2) would determine whether the 3D geometric aspects of the assay actually influence occupancy of the Tepui tops.…”

mentioning

confidence: 99%

“…High densities of cancer cells of different metastatic potential are deposited at the foot of the Tepuis and allowed to climb along the Tepuis until they reach their tops. Both the rate at which the Tepuis tops are reached and the fractions of Tepuis tops that are occupied are monitored (2).…”

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confidence: 99%

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Recapitulating cancer cell invasion in vitro

Kim¹,

Wirtz²

2011

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

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C onfocal microscopy can visualize cancer cell metastasis in the vicinity of a primary tumor site in animal models of cancer in real time. However, spatial resolution of current microscopes in vivo remains limited and subcellular structures cannot be readily imaged, reducing the molecular mechanistic insights that can be directly obtained from in vivo models of cancer metastasis. Moreover, therapeutic approaches that are successful in rodent models do not always translate into actual therapeutic approaches to human cancers. Hence, in vitro models remain useful not only to further our basic understanding of cancer cell biology and the metastatic cascade but also for clinical applications, such as high-throughput drug screening and testing. In particular, in vitro structures that acknowledge the three-

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Microfabricated Systems and Assays for Studying the Cytoskeletal Organization, Micromechanics, and Motility Patterns of Cancerous Cells

Huda

Pilans

Makurath

et al. 2014

Adv Materials Inter

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Cell motions are driven by coordinated actions of the intracellular cytoskeleton – actin, microtubules (MTs) and substrate/focal adhesions (FAs). This coordination is altered in metastatic cancer cells resulting in deregulated and increased cellular motility. Microfabrication tools, including photolithography, micromolding, microcontact printing, wet stamping and microfluidic devices have emerged as a powerful set of experimental tools with which to probe and define the differences in cytoskeleton organization/dynamics and cell motility patterns in non-metastatic and metastatic cancer cells. In this review, we discuss four categories of microfabricated systems: (i) micropatterned substrates for studying of cell motility sub-processes (for example, MT targeting of FAs or cell polarization); (ii) systems for studying cell mechanical properties, (iii) systems for probing overall cell motility patterns within challenging geometric confines relevant to metastasis (for example, linear and ratchet geometries), and (iv) microfluidic devices that incorporate co-cultures of multiple cells types and chemical gradients to mimic in vivo intravasation/extravasation steps of metastasis. Together, these systems allow for creating controlled microenvironments that not only mimic complex soft tissues, but are also compatible with live cell high-resolution imaging and quantitative analysis of single cell behavior.

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Probing the invasiveness of prostate cancer cells in a 3D microfabricated landscape

Cited by 37 publications

References 26 publications

Minimization of thermodynamic costs in cancer cell invasion

Minimization of thermodynamic costs in cancer cell invasion

Recapitulating cancer cell invasion in vitro

Microfabricated Systems and Assays for Studying the Cytoskeletal Organization, Micromechanics, and Motility Patterns of Cancerous Cells

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