The role of Rho GTPase in cell stiffness and cisplatin resistance in ovarian cancer cells

Sharma, Shivani; Santiskulvong, Chintda; Rao, Jianyu; Gimzewski, James K.; Dorigo, Oliver

doi:10.1039/c3ib40246k

Cited by 71 publications

(60 citation statements)

References 21 publications

(28 reference statements)

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“…Moreover, cell mechanotype can identify cells that are resistant to common chemotherapy drugs. Cisplatin‐resistant ovarian cancer cells are less deformable due to modification of their actin cytoskeleton 97 . The altered mechanotype of chemoresistant cells can be utilized in large‐scale drug screening using cell deformability as a readout; mechanotype measurements are advantageous for high‐throughput screening as an inexpensive, label‐free approach.…”

Section: Clinical Impact and Potential Targets For Therapeutic Benefitsupporting

confidence: 61%

Neural regulation of cancer: from mechanobiology to inflammation

Kim

Rowat

Sloan³

2016

Clin & Trans Imm

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Despite recent progress in cancer research, the exact nature of malignant transformation and its progression is still not fully understood. Particularly metastasis, which accounts for most cancer death, is a very complex process, and new treatment strategies require a more comprehensive understanding of underlying regulatory mechanisms. Recently, the sympathetic nervous system (SNS) has been implicated in cancer progression and beta-blockers have been identified as a novel strategy to limit metastasis. This review discusses evidence that SNS signaling regulates metastasis by modulating the physical characteristics of tumor cells, tumor-associated immune cells and the extracellular matrix (ECM). Altered mechanotype is an emerging hallmark of cancer cells that is linked to invasive phenotype and treatment resistance. Mechanotype also influences crosstalk between tumor cells and their environment, and may thus have a critical role in cancer progression. First, we discuss how neural signaling regulates metastasis and how SNS signaling regulates both biochemical and mechanical properties of tumor cells, immune cells and the ECM. We then review our current knowledge of the mechanobiology of cancer with a focus on metastasis. Next, we discuss links between SNS activity and tumor-associated inflammation, the mechanical properties of immune cells, and how the physical properties of the ECM regulate cancer and metastasis. Finally, we discuss the potential for clinical translation of our knowledge of cancer mechanobiology to improve diagnosis and treatment.

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Section: Clinical Impact and Potential Targets For Therapeutic Benefitsupporting

confidence: 61%

Neural regulation of cancer: from mechanobiology to inflammation

Kim

Rowat

Sloan³

2016

Clin & Trans Imm

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“…Indeed, the anti-cancer drug SAHA causes a change in cell stiffness and a change in malignancy, which might be due to this change in stiffness [28]. In addition, increased cell stiffness has been correlated with drug resistance [29], pointing to another connection between cancer therapy and stiffness.…”

Section: Introductionmentioning

confidence: 99%

The effect of neighboring cells on the stiffness of cancerous and non-cancerous human mammary epithelial cells

et al. 2014

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Using an Atomic Force Microscope (AFM) with a 5.3 μm diameter spherical probe, we determined mechanical properties of individual human mammary epithelial cells. The cells were derived from a pair of cell lines that mimic cell progression through four phases of neoplastic transformation: normal (nontransformed), immortal, tumorigenic, and metastatic. Measurements on cells in all four phases were taken over both the cytoplasmic and nuclear regions. Moreover, the measurements were made for cells in different microenvironments as related to cell-cell contacts: isolated cells; cells residing on the periphery of a contiguous cell monolayer; and cells on the inside of a contiguous cell monolayer. By fitting the AFM force versus indentation curves to a Hertz model, we determined the pseudo-elastic Young's modulus, E. Combining all data for the cellular subregions (over nucleus and cytoplasm) and the different cell microenvironments, we obtained stiffness values for normal, immortal, tumorigenic, and metastatic cells of 870 Pa, 870 Pa, 490 Pa, and 580 Pa, respectively. That is, cells become softer as they advance to the tumorigenic phase and then stiffen somewhat in the final step to metastatic cells. We also found a distinct contrast in the influence of a cell's microenvironment on cell stiffness. Normal mammary epithelial cells inside a monolayer are stiffer than peripheral cells, which are stiffer than isolated cells. However, the microenvironment had a slight, opposite

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“…Our finding that paclitaxel and dual drug-resistant ovarian cancer cells are significantly softer than drug-sensitive ovarian cancer cells is consistent with these reports. Though we have found cisplatin-resistant cells also to be softer than drug-sensitive cells, recent studies with cisplatin-resistant ovarian cancer cells have reported the reverse trend of increased cell stiffness with drug resistance (Sharma et al 2014). The divergence of our findings with this study may have arisen due to several factors.…”

Section: Discussionmentioning

confidence: 48%

Soft drug-resistant ovarian cancer cells invade via two distinct mechanisms utilizing myosin IIB

Kapoor

Thakur

Monteiro

et al. 2017

Preprint

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The failure of chemotherapeutic drugs in treatment of various cancers is attributed to the acquisition of drug resistance. However, the invasion mechanisms of drug-resistant cancer cells remains incompletely understood. Here we address this question from a biophysical perspective by mapping the phenotypic alterations in ovarian cancer cells (OCCs) resistant to cisplatin and paclitaxel. We show that cisplatin-resistant (CisR), paclitaxel-resistant (PacR) and dual drug-resistant (i.e., resistant to both drugs) OCCs are softer and more contractile than drug-sensitive cells. Protease inhibition suppresses invasion of CisR cells but not of PacR and dual cells, suggesting protease-dependent mode of invasion in CisR cells and protease-independent mode in PacR and dual cells. Despite these differences, actomyosin contractility, mediated by the RhoA-ROCK2-Myosin IIB signaling pathway regulates both modes of invasion.Myosin IIB modulates matrix metalloproteinase-9 (MMP-9) secretion in CisR cells and nuclear squeezing in PacR and dual cells, thereby highlighting its importance as a potential therapeutic target for treatment of drug-resistant ovarian cancer cells.

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The role of Rho GTPase in cell stiffness and cisplatin resistance in ovarian cancer cells

Cited by 71 publications

References 21 publications

Neural regulation of cancer: from mechanobiology to inflammation

Neural regulation of cancer: from mechanobiology to inflammation

The effect of neighboring cells on the stiffness of cancerous and non-cancerous human mammary epithelial cells

Soft drug-resistant ovarian cancer cells invade via two distinct mechanisms utilizing myosin IIB

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