We have reported several years ago the 5-year-old male patient with Li-Fraumeni syndrome with osteosarcoma and atypical type of hepatic cancer. Intriguingly, the cancer stem cell marker CD44 variant was ectopically induced after chemotherapy probably due to the selective pressure of excessive reactive oxygen species (ROS) provoked by chemotherapy.
I am appreciated if you would give me some feedback or comment on the following article.
Li-Fraumeni syndrome with simultaneous osteosarcoma and liver cancer: Increased expression of a CD44 variant isoform after chemotherapy
BMC Cancer2012;12:444
https://doi.org/10.1186/1471-2407-12-444
Interesting question. There is evidence that people with LFS have high basal levels of oxidative stress - and that this may be related to the process of carcinogenesis (see Article Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche
). Is it possible that the high levels of CD44 expression reflect high background oxidative stress?
I am appreciated for your kind comment.
It has been shown that CD44 variant 8-10 (CD44v), produced by the alternative splicing machinery regulated by ESRP1 protein, contributes to the attenuation of high level of redox stress in the tumor microenvironment.
My colleagues and I have demonstrated that CD44v interacts with and stabilizes the protein xCT at the cell membrane. This latter protein, together with CD98 heavy chain, forms an antiporter known as system Xc(−) that exchanges intracellular glutamate for extracellular cystine. Cysteine as well as glycine and glutamate are essential substrates for synthesis of GSH. CD44v8–10 thus promotes GSH synthesis by increasing the import of cystine and thereby increasing the intracellular concentration of cysteine. The elimination of ROS by GSH inhibits the activation of p38 MAPK signaling and thereby prevents ROS-induced senescence, apoptosis, or differentiation of cancer cells. The CD44v8–10–xCT–GSH axis thus protects CSCs from redox stress.
Ref.
* Inversed relationship between CD44 variant and c-Myc due to oxidative stress-induced canonical Wnt activation.
Biochem Biophys Res Commun. 2014 Jan 10;443(2):622-7.
* Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell.
Nat Commun. 2012 Jun 6;3:883.
* Therapeutic strategies targeting cancer stem cells. (Review)
Cancer Sci. 2016 Jan;107(1):5-11.
Sincerely yours
Go J. Yoshida MD, PhD.
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