The link between a prognostic marker and a vulnerable survival mechanism
There may be a connection between the prognostic value of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and the presence of cancer stem cells (CSCs) and differentiated cancer cells that are susceptible to reactive oxygen species (ROS)–generating therapeutic strategies.1-4
pSTAT3 as a poor prognostic indicator
Overexpression of pSTAT3 has been associated with poorer overall survival, the presence of lymph node metastases in patients with colorectal cancer (CRC), and worse patient outcomes in metastatic CRC (mCRC), regardless of other factors.3,4 This may be associated with the inflammatory environment created by CSCs and differentiated cancer cells that endure due to a unique redox balance.1,2
What is the difference between ROS and ROS1?
ROS is an abbreviation for reactive oxygen species, highly chemically reactive compounds derived from molecular oxygen, including free radicals, which may be cytotoxic.5,6
This is a term distinct from ROS1, a protein kinase that is expressed aberrantly in some cancers and thus becomes a therapeutic target, most notably in some types of lung cancer.7
Redox balance and cancer cell survival
All human cells balance naturally occurring ROS with compensatory antioxidants. A subset of CSCs and differentiated cancer cells may survive due to a unique redox balance that enables them to persist despite levels of ROS which would normally be disruptive.2,5,8
Adapted from Taverne et al. Oxid Med Cell Longev. 2013.9
Targeting oxidative stress resistance
CSCs and differentiated cancer cells that persist due to a unique redox balance may be susceptible to therapeutic approaches that generate high levels of ROS, which can outpace their antioxidant compensation, upset their redox balance, and trigger cell death.1,2
Subset activation of STAT3
This subset of CSCs and differentiated cancer cells may also secrete increased levels of inflammatory proteins, activating a signaling protein called STAT3. The activated form of STAT3 is known as phosphorylated STAT3, or pSTAT3.1,2
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- Chang AY, Hsu E, Patel J, et al. Evaluation of tumor cell-tumor microenvironment component interactions as potential predictors of patient response to napabucasin. Mol Cancer Res. 2019; 17(7):1429-1434.
- Madajewski B, Boatman MA, Chakrabarti G, Boothman DA, Bey EA. Depleting tumor-NQO1 potentiates anoikis and inhibits growth of NSCLC. Mol Cancer Res. 2016;14(1):14-25.
- Ji K, Zhang M, Chu Q, et al. The role of p-STAT3 as a prognostic and clinicopathological marker in colorectal cancer: a systematic review and meta-analysis. PLOS ONE. 2016;11(8):e0160125. doi:10.1371/journal.pone.0160125.
- Dobi E, Monnien F, Kim S, et al. Impact of STAT3 phosphorylation on the clinical effectiveness of anti-EGFR–based therapy in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2013;12(1):28-36. doi:10.1016/j.clcc.2012.09.002.
- Ding S, Li C, Cheng N, Cui X, Xu X, Zhou G. Redox regulation in cancer stem cells. Oxid Med Cell Longev. 2015;2015:750798.
- Liu J, Wang Z. Increased oxidative stress as a selective anticancer therapy. Oxid Med Cell Longev. 2015;2015:294303. doi:10.1155/2015/294303.
- Sokolenko AP, Imyanitov EN. Molecular diagnostics in clinical oncology. Front Mol Sci. 2018;5:76. doi:10.3389/fmolb.2018.00076.
- Lee HY, Parkinson EI, Granchi C, et al. Reactive oxygen species synergize to potently and selectively induce cancer cell death. ACS Chem Biol. 2017;12(5):1416-1424.
- Taverne Y, Bogers A, Duncker D, Merkus D. Reactive oxygen species and the cardiovascular system. Oxid Med Cell Longev. 2013; 2013:862423. doi:10.1155/2013/862423.