Mechanical Stretch Kills Transformed Cancer Cells
Preprint posted on 10 December 2018 https://www.biorxiv.org/content/10.1101/491746v2
A hallmark of transformed cancer cells is their ability to grow on soft substrate, which is often correlated with their loss of matrix rigidity-sensing ability 1. Previous studies demonstrated that alteration in expression of cytoskeleton proteins in transformed cancer cells could restore rigidity sensing and help in blocking growth 2,3. Recent studies have provided some evidence in support of mechanical force-dependent growth inhibition in a mice model; gentle stretching of mice (10 minutes of stretching/day for 4-weeks) resulted in inhibition of tumor growth 4,5. Authors of this preprint report a very intriguing finding that transformed cancer cells from various tissue origins, when subjected to cyclic mechanical stretching, inhibit their growth and undergo apoptosis.
The authors show that 6 hours of cyclic stretching of rigidity-dependent transformed cancer cells, which lack expression of cytoskeletal protein TPM2.1 (key protein in rigidity sensing 6), results in cell elongation. Exogenous expression of TPM2.1 could restore rigidity sensing, and inhibited cyclic-stretching-dependent cell elongation. Further, the authors report that cyclic stretching inhibited the growth of transformed cells, while facilitating normal cell growth. This was attributed to increased apoptosis in transformed cells and reduced apoptosis in normal cells upon cyclic stretching.
The authors perform elegant experiments to elucidate a mechanistic pathway of this process: cyclic stretching results in increases in the influx of calcium, which activates calpain protease. This further acts on Bax to induce the mitochondrial apoptotic pathway, eventually leading to cell death.
Importance and Future questions
This study reveals that mechanical sensitivity of tumor cells is related to transformed cell state and not linked to tissue origin or cell type. This raises the possibility to exploit this process in animal models to specifically damage tumor cells and simultaneously promote normal cell growth. These findings will help in understanding and designing a better set up to utilize mechanical force based therapy.
It would be interesting to see when the growth of “normal cells” post cyclic stretching comes down to the non-stretched state. Do the normal cells in a mixture of transformed cancer cells have a mechanoprotective role?
- Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
- Yang, B. et al. Stopping Transformed Growth with Cytoskeletal Proteins: Turning a Devil into an Angel. bioRxiv 221176 (2018). doi:10.1101/221176
- Wolfenson, H. et al. Tropomyosin controls sarcomere-like contractions for rigidity sensing and suppressing growth on soft matrices. Nat. Cell Biol. 18, 33–42 (2016).
- Berrueta, L. et al. Stretching Reduces Tumor Growth in a Mouse Breast Cancer Model. Sci. Rep. 8, 7864 (2018).
- Betof, A. S. et al. Modulation of Murine Breast Tumor Vascularity, Hypoxia, and Chemotherapeutic Response by Exercise. JNCI J. Natl. Cancer Inst. 107, (2015).
- Stehn, J. R. et al. A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells. Cancer Res. 73, 5169–5182 (2013).
Posted on: 5 February 2019Read preprint
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