Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression
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- 作者：Dhivya Sridaran ; Ganesan Ramamoorthi ; Rasool MahaboobKhan…
- 关键词：Tumor microenvironment ; Oxidative stress ; EMT ; Metabolic reprogramming ; Cancer progression
- 刊名：Tumor Biology
- 出版年：2016
- 出版时间：October 2016
- 年：2016
- 卷：37
- 期：10
- 页码：13307-13322
- 全文大小：2,770 KB
- 刊物主题：Cancer Research;
- 出版者：Springer Netherlands
- ISSN：1423-0380
- 卷排序：37
文摘
During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment (TM) that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention.