We are interested in the dynamics of quiescent and proliferative cancer stem cells (CSCs) when tumor tissue shows invasion. We have previously investigated into the expression level of CD44 variant 8-10 (CD44v8-10), one of the reliable cancer stem cell markers, in parallel with proto-oncogenic molecule c-Myc, the expression of which is supported by redox stress-induced Wnt/beta-catenin signal pathway. CD44v8-10-positive cancer cells are enriched at the invasive front of the gastric and breast cancer. Tumor tissue at the invasive area is considered to be composed of heterogeneous cellular population; dormant cancer stem-like cells with CD44v8-10 (high)/ Fbw7 (high)/ c-Myc (low) and proliferative cancer stem-like cells with CD44v8-10 (high)/ Fbw7 (low)/ c-Myc (high). The heterogeneity of E3-ubiquitin ligase Fbw7 expression in a cancer cell-autonomous manner is responsible for the co-existence of quiescent and proliferative CSCs at the invasive front (Biochem Biophys Res Commun. 2014 Jan 10;443(2):622-7.).
Furthermore, metastatic potential of B16F1 melanoma cells in Mx1-Cre Fbxw7Δ/Δ mice has recently suggested that Fbw7 ablation in bone marrow-derived stromal cells (BMSCs) induced accumulation of Notch intracellular domain and consequent transcriptional activation of Ccl2. Fbw7-deficient mice exhibited increased serum levels of the chemokine CCL2, thereby promoting metastatic tumor growth. Fbw7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis of human breast cancer patients (J Clin Invest. 2015 Jan 2. pii: 78782.).
To be sure, Nakayama K, et al emphasized that Fbw7 antagonizes tumor invasion in not only a cell-autonomous manner, but also a non-cell-autonomous manner in terms of Fbw7/Notch/CCL2 axis,
I wonder whether or not Fbw7 expression changees at the invasive front is regulated in a cancer cell-autonomous or non-cell-autonomous manner in terms of oxidative stress and canonical Wnt signal. Furthermore, CSCs are really enriched at the invasive front in the heterogeneous manner of the G0 and Galert phase?
I would appreciate if you would give your opinion and perspective.
http://www.ncbi.nlm.nih.gov/pubmed/25555218
http://www.ncbi.nlm.nih.gov/pubmed/24333422
In the bone marrow is a stem cell, the hemocytoblast, which differentiates into various types of blood cells. This stem cell, hich may be considered as a 'mother cell' has low proliferative potential; it is the daughter cells that proliferate. This is natures safety mechanism, so that DNA damage is less likely in the stem cells (less proliferation lesser risk of DNA damage' and also its expression. . Presence of stem cells is a feature of hierachical type of tissues such as skin, mucosa, etc too. If such a stem cell turns malignant, it may will be a Cancer stem cell (CSC) or any tumour may have CSCs. Since they have low proliferatiion rate, they will be relatively resistant to chemo/radiotherapy, and thus cause recurrence. There may be need of targeted therapies for their killing.
Your question is about 'dormant and proliferative' stem cells; I think it may be wrong to call a proliferating cell as CSC since they are not; of course they occasionally divide, but I don't think they fall into proliferative category.
Another point I would make is that all cells in the invasive front of a tumour is likely to proliferative, and CSC are unlikely to be present there; they are more likely to be near the central, potentially necrotic area.
My suggestion would be study cytological indicators of cell division such as micro+bi+multinucleation (it can be studied easily using imprint smears; see my papers in research gate) from the periphery and correlate with the given markers.
Thank you for your comment.
The heterogeneous expression of Ki-67 at the invasive front makes it difficult to determine whether or not all cells in the invasive front of a tumour is likely to proliferative. Needless to say, hypoxic central tumor area is composed of a large number of CSCs.
As you have suggested, I will compare the CSC marker expression for the comparison between central and peripheral invasive area. It is likely, however, that the result is highly likely to depend on the kind of tumor or pathological subtype.
Yes, true. When collecting tissue, just take an imprint smear and see the big, micro,
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