Though the preparations on the previous (post) mini hypothesis and giving me opportunities to read number of literatures as well as guiding me to have some depth overview on the stem-cell niche field, interestingly it’s also leaving me number of curiosity questions. such as,
I) on the part of cell-fusion:
i) In general or within the context of cancer, are there any relationships between cell-fusion and the G0/G1 cell cycle?
(thought provoking key paper:
Lizard G etal in Cell fusion of human and mouse cells as a source for new cells retaining human markers. Analysis of DNA content, membrane and cytoplasmic antigen expression. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60(5):301-6
ii) After cell-fusion followed by reductive division explain about the presence of epithelial-mesenchymal transition (EMT) markers in the newly formed cells. Is this reductive division have any relationship with senescence?
(Key paper:
Krtolica A etal Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12072-7. Epub 2001 Oct 2)
iii) Does the cell fusion process also occur between the 'cancer-associated fibroblast' (CAFs) and endothelial progenitor cells (which is recruited by CAFs)?
II) on the part of therapeutic targets:
i) apart from the identification of metalloproteinases in cancer-associated fibroblast (CAFs) (1) until now there is only one Tyrosine protein kinase (Platelet-Derived Growth Factor (PDGF), a PDGFR family) has been studied /correlated with the CAFs cells (2) so could this PDGF become a molecular therapeutic target of CAFs?
Key papers:
1.Rosenthal EL Expression of proteolytic enzymes in head and neck cancer-associated fibroblasts. Arch Otolaryngol Head Neck Surg. 2004 Aug;130(8):943-7)
2. Mueller L Imatinib mesylate inhibits proliferation and modulates cytokine expression of human cancer-associated stromal fibroblasts from colorectal metastases Cancer Lett. 2007 Jun 8; 250(2):329-38. Epub 2006 Dec 4.).
ii) Interestingly, one of the CAFs secretary factor know as S100A4 has a binding site for TCF (t-cell receptor) as well as play role with beta-catenin. So could it also become as a therapeutic target for any metastasis cancer, by interrupting their cell-cell interactions (for examples), ...?
(key paper:
Stein U etal The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer. Gastroenterology. 2006 Nov; 131(5):1486-500. Epub 2006 Aug 22)
III) in general:
i) Once a lesion initiated, CAFs have been shown to assist in proliferation and progression of cancer through the production of growth factors, chemotactic factors, angiogenesis factors, matrix metalloproteinases MMPs towards invasion and spread of cancer cells in initiated, non tumorogenic epithelial cells. Since CAFs playing the tumorigenic role within the cancer microenvironment, its ability to form cancer, ability to attract progenitors, ability to transform epithelial cells, etc shall we call these 'cancer-associated fibroblast' (CAFs) as an “unipotent progenitor cells” or ‘fibroblast-restricted progenitor cells’?
In other words, still it’s not clear why most late-life cancers are epithelial. Since CAFs have role in senescence (1) shall we expect that the CAFs may undergo reverse phenotype (so it could able to escape from the immune system) and express its tumorogentic behaviours in those late-life cancer?
(key paper:
Krtolica A etal Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging Proc Natl Acad Sci U S A. 2001 Oct 9; 98(21):12072-7. Epub 2001 Oct 2)
ii) within the stromal-cancer microenvironment, while both cancer and the CAFs cells come together, there might be possibility of excess production of the growth factor such as S100A4, SDS???, etc. does this increase level of gradients makes any effects on their behaviour (within the niche / microenvironment)?
iv) Unclear part:
its not clear if
i) there is any role of epigenetic alterations Vs CAFs, within the context of aberrant tumor microenvironment?
ii) whether the bone marrow derived (stem) cells Vs CAFs as well as cancer stem-cell Vs stromal cells share any common genetic origins?
iii) whether the cancer stem-cells also produce the CAFs?
I would be grateful if you could offer or share any of your thoughts on these questions, which would ultimately helpful for me to improve some knowledge on the field of stem-cell niche in normal and pathologic conditions . Thank you!
Have a nice day!
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