The role of heterogeneous environment and docetaxel gradient in the emergence of polyploid, mesenchymal and resistant prostate cancer cells

Clinical & Experimental Metastasis
Ke-Chih LinRobert Austin

Abstract

The ability of a population of PC3 prostate epithelial cancer cells to become resistant to docetaxel therapy and progress to a mesenchymal state remains a fundamental problem. The progression towards resistance is difficult to directly study in heterogeneous ecological environments such as tumors. In this work, we use a micro-fabricated "evolution accelerator" environment to create a complex heterogeneous yet controllable in-vitro environment with a spatially-varying drug concentration. With such a structure we observe the rapid emergence of a surprisingly large number of polyploid giant cancer cells (PGCCs) in regions of very high drug concentration, which does not occur in conventional cell culture of uniform concentration. This emergence of PGCCs in a high drug environment is due to migration of diploid epithelial cells from regions of low drug concentration, where they proliferate, to regions of high drug concentration, where they rapidly convert to PGCCs. Such a mechanism can only occur in spatially-varying rather than homogeneous environments. Further, PGCCs exhibit increased expression of the mesenchymal marker ZEB1 in the same high-drug regions where they are formed, suggesting the possible induction of an epithelial to...Continue Reading

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Citations

Sep 22, 2020·Evolutionary Applications·Kenneth J PientaSarah R Amend
Nov 5, 2019·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Luca AndreiMilica Pešić
Nov 30, 2019·Cytokine & Growth Factor Reviews·Deblina Bharadwaj, Mahitosh Mandal
Nov 4, 2020·Cold Spring Harbor Perspectives in Medicine·Robert A Gatenby, Joel S Brown
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Dec 5, 2020·Seminars in Cancer Biology·K J PientaS R Amend
Mar 18, 2021·Seminars in Cancer Biology·Halina WasClaudine Kieda
Dec 7, 2020·Bone·Mikaela M MallinSarah R Amend
May 21, 2021·Advanced Drug Delivery Reviews·Nuala Del PiccoloSteven C George
Jun 28, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Milad AshrafizadehSaeed Samarghandian
Jul 2, 2021·Frontiers in Cell and Developmental Biology·Jing Christine YeHenry H Heng
Sep 29, 2021·Medical Oncology·Laurie G KosteckaSarah R Amend

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ImageJ
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