Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression
- 291 Downloads
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.
KeywordsTumor microenvironment Oxidative stress EMT Metabolic reprogramming Cancer progression
This work was supported by DST-SERB (No. SB/EMEQ-082/2013) Project and University Grants Commission [UGC F. No. 37–109/2009 (SR)], India. SD was supported by Lady Tata Memorial Research Fellowship 2014.
Compliance with ethical standards
Conflicts of interest
- 10.Seluanov A, Vaidya A, Gorbunova V. Establishing primary adult fibroblast cultures from rodents. J Vis Exp. 2010;44:2033.Google Scholar
- 15.Moss DW, Henderson AR. Determination of lactate dehydrogenase activity by measurement of NADH consumption. Second edition ed. Tietz Text Book. Clin Chem Phila. 1994; p 816–818.Google Scholar
- 23.Wlassoff WA, Albright CD, Sivashinski MS, et al. Hydrogen peroxide overproduced in breast cancer cells can serve as an anticancer prodrug generating apoptosis-stimulating hydroxyl radicals under the effect of tamoxifen-ferrocene conjugate. J Pharm Pharmacol. 2007;59(11):1549–53.CrossRefPubMedGoogle Scholar
- 48.Krawczyk N, Meier-Stiegen F, Banys M, et al. Expression of stem cell and epithelial-mesenchymal transition markers in circulating tumor cells of breast cancer patients. Biomed Res Int. 2014:415721.Google Scholar