Metformin & the Epithelial–Mesenchymal transition [EMT]

New study below [1].

The title of this post may have put some off from reading, but the Epithelial–Mesenchymal transition [EMT] concept is fairly easy to grasp.

PCa develops in prostatic epithelial cells. These cells are mot particularly mobile. A key event in metastasis is the transformation of the epithelial cell to a stem-cell-like mesenchymal cell. It's quite an extraordinary trick. The cell simply morphs into something quite different.

The transformed cells are very mobile. Those that are able to find a hospitable docking site, then transform themselves back to epitherilal cells, via MET - the reverse of EMT.

"Initiation of metastasis requires invasion, which is enabled by EMT. Carcinoma cells in primary tumor lose cell-cell adhesion mediated by E-cadherin repression and break through the basement membrane with increased invasive properties, and enter the bloodstream through intravasation. Later, when these circulating tumor cells (CTCs) exit the bloodstream to form micrometastases, they undergo MET for clonal outgrowth at these metastatic sites. Thus, EMT and MET form the initiation and completion of the invasion-metastasis cascade." [2]

EMT is a downside to ADT. "Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression." [3]

In May, it was reported that Simvastatin could block EMT [4].

In January, that Valproic acid inhibits EMT [5].

From 2015 - Apigenin inhibits EMT [6].

& 2014: Muscadine grape skin extract too [7].

Two 2014 papers had already indicated that Metformin could inhibit EMT [8] [9].

From the new paper: "Activation of inflammatory signaling pathway and initiation of epithelial-mesenchymal transition (EMT) are closely related to drug resistance, tumor relapseas well as metastasis. In this study, we demonstrated that metformin is capable of inhibiting prostate cancer cell migration and invasion by repressing EMT evidenced by downregulating the mesenchymal markers N-cadherin, Vimentin, and Twist and upregulating the epithelium E-cadherin. These effects have also been observed in our animal model as well as prostate cancer patients." [1]

"These findings suggest that metformin by itself or in combination with other anticancer drugs could be used as an anti-metastasis therapy."

It's an intriguing idea that newly diagnosed patients might largely avoid metastatic disease by using Metformin. But even when metastases are present, I think it beneficial to shut off the tap.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/280...

[2] en.wikipedia.org/wiki/Epith...–mesenchymal_transition

[3] ncbi.nlm.nih.gov/pubmed/255...

[4] ncbi.nlm.nih.gov/pubmed/271...

[5] ncbi.nlm.nih.gov/pubmed/262...

[6] ncbi.nlm.nih.gov/pubmed/253...

[7] ncbi.nlm.nih.gov/pubmed/246...

[8] ncbi.nlm.nih.gov/pubmed/252...

[9] ncbi.nlm.nih.gov/pubmed/246...

5 Replies

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  • Patrick,

    Muscadine grape skin extract; how much per day would need to be used by a human being. Where can I buy it, in pill or liquid form. I can't drink the wine.

    Rich

  • The understanding of the transition of prostate cells into circulating tumor cells and then into metastatic cells is very important. If we could keep cells out of the blood, or kill them there, I think it is clear that this would be a major step forward.

    It may be that some early prostate cells are kicked out of the prostate by tumor associated macrophages (TAMs), which could be viewed as an attempt by the immune system to deal with the cancer by tossing them out of the prostate. This strategy works for a while. My take on it.

    Here is Ken Pienta on the neuro endocrine variant, aka "small cell".

  • I must believe this EMT/MET process is the scientific basis for Dr. Charles "Snuffy" Myers prescribing high dose Metformin for his patients. I have been taking 1000mg twice a day for almost 4 years and I am still above ground! PSA=29, Gleason=10, and many lymph node mets at diagnosis in August 2012.

  • I think what Patrick is saying, is that as soon as you have had your initial treatment, such as RP, before cell transformation, to then attack with Metformin, or the other materials mentioned. For me it was Metformin, and the Muscadine. For the gentleman looking to get the grape skin and seed extract, you can go to Vitacost.com--and they have a good product under the Vitacost label.

    Nalakrats

  • Very interesting Patrick - thanks for posting!

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