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Removal of senescent cells via Epithelial-to-Mesenchymal transition

Image credit: Riki okita et al., 2018 http://jtd.amegroups.com/article/view/23392/html

Shubhankar Kulkarni
Shubhankar Kulkarni Aug 06, 2020
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Senescent cells can be present in inacessible regions of tissues in the body. Removal, therefore, is a daunting task. Epithelial-to-mesenchymal transition (EMT) is a developmental phenomenon where attached cells break free and enter the circulation. Tumor cells exploit EMT to cause metastasis. Different agents of EMT induction have also been identified.

Removal of senescent cells is already being researched to target the aging phenotype. EMT, specifically targetted towards senescent cells (using markers specific to the senescent cells), can be artificially induced to make them motile. These cells will then enter the circulation and can be removed via dialysis.

[1]Maithilee Khot, Dyuthi Sreekumar, Sanika Jahagirdar, Apoorva Kulkarni, Kishore Hari, Elangoli Ebrahimkutty Faseela, Radhakrishnan Sabarinathan, Mohit Kumar Jolly, Kundan Sengupta, Twist1 induces chromosomal instability (CIN) in colorectal cancer cells, Human Molecular Genetics, Volume 29, Issue 10, 15 May 2020, Pages 1673–1688, https://doi.org/10.1093/hmg/ddaa076

[2]Okita R, Shimizu K, Nakata M. Epithelial-mesenchymal transition-induced metastasis could be a bait for natural killer cells. J Thorac Dis 2018;10(Suppl 26):S3143-S3146. doi: 10.21037/jtd.2018.08.19

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General comments

Muhammad M Rahman
Muhammad M Rahman3 years ago
In principle this is a great idea however the problem arises where you have senescent cancer stem cells. One particular paper and its review (Senescence-associated reprogramming promotes cancer stemness, 2018 and Senescence Elicits Stemness: A Surprising Mechanism for Cancer Relapse, 2018) suggest that senescence can promote stemness which in the context of cancer stem cells, would make these cell more tumourigenic. One way in which cancer stem cells are more aggressive is through increased EMT so yes, you could use this to get cells into the blood but if the senescent cancer cell isn’t removed it is likely to develop into a tumour elsewhere in the body. Furthermore, targeting cancer stem cells is very difficult as they are more resistant to UV and chemotherapies. Following your train of thought, perhaps using multiple markers to detect senescent cells and cancer stem cells would work.
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Darko Savic
Darko Savic4 years ago
I don't remember where I got this from (so no reference) but virus-infected cells are known to detach. Could we engineer an appropriate virus that will cause said detachment, to target specifically Senescent cells?
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Shubhankar Kulkarni
Shubhankar Kulkarni4 years ago
Darko Savic Great idea! Here is a reference: The Ebola virus envelope glycoprotein (GP) mediated cell detachment from the extracellular matrix in 293T cells. A reduction in cell surface expression of adhesion molecules such as integrin β1, major histocompatibility complex class I, and the epidermal growth factor receptor was observed with the loss of cell adhesion. Furthermore, the Ebola virus GP did not increase cell death while causing cell detachment. Also, the cells were able to readhere and continue to divide once the GP expression was modulated. Even the replication-deficient adenovirus vectors expressing Ebola virus GP could induce the loss of cell adhesion in endothelial cells and macrophages.

Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC153797/
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jnikola4 years ago
Let's say we have acutely or chronically damaged cells that can either be fixed or turn apoptotic, senescent, or tumorigenic. Our cells „pick“ the road of senescence. ----- Once alive and a threat, these cells are now „put to sleep“. They still can affect aging and promote tumor development by secretion of specific factors (doi:10.1038/nrm3823, doi: 10.5772/54120), so we want them out of the system. Besides, clearing senescent cells showed a significant effect on tissue homeostasis and aging (doi:10.1016/j.cell.2017.02.031), so we are eager to remove them, possibly without „waking them up“! ----- EMT is a transition process that metabolically active and dividing cells sometimes „use“ to become motile and spread (fibrosis, metastasis). So, for that, we need cells that are „awake“ and somewhat safe, unless we want a tumor! ----- While figuring it out, I bumped on a few articles stating that some molecular mechanisms that regulate these two processes are crossing paths. Transcription factors like Twist and Zeb1 can simultaneously both inhibit senescence and induce EMT (doi:10.1038/s41420-020-0286-z, doi:10.18632/aging.100209). It would be a perfect tool for the above-mentioned idea, but could easily go wrong and promote tumor progression in “awaken” cells. -----> So, if we somehow manage to specifically target only the senescent cells in inaccessible regions of tissues and turn them motile (using Zeb1, for example), wouldn't that be the awakening of the Frankenstein? Can we perform dialysis cells faster than small Frankensteins do bigger damage, or we need a faster clearance tool, already waiting in the bloodstream?
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Shubhankar Kulkarni
Shubhankar Kulkarni4 years ago
Hi Juran! Thank you for the comment. Performing dialysis and clearing the senescent cells is the ultimate goal. For that, we need to remove the senescent cells from the inaccessible places and make them enter the bloodstream. Based on your comment, now I think we can use Twist or Zeb1 in combination with senolytics or dialysis to get the desired effect.
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