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EJINME-03344; No of Pages 1

EJINME-03344; No of Pages 1

European Journal of Internal Medicine xxx (2016) xxx

Pages 1 European Journal of Internal Medicine xxx (2016) xxx Contents lists available at ScienceDirect European

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Medicine journal homepage: www.elsevier.com/locate/ejim Letter to the Editor Antineoplastic potential of metformin

Letter to the Editor

Antineoplastic potential of metformin in colorectal cancer

Keywords:

Metformin

Neoplasms

Colorectal neoplasms

Colonic polyps

Diabetes mellitus

KRAS

Dear Editor,

I read with interest the article Colon neoplasia in patients with type 2 diabetes on metformin: A meta-analysisby Rokkas and Portincasa [1]. As the authors note, the mechanisms underlying the antineoplastic potential of metformin in colon neoplasia are probably manifold and not yet completely understood. Experimental data support a direct effect of metformin in antagonizing specic pathways that promote cell prolifer- ation, motility, invasion, and migration. As Rokkas and Portincasa mention, metformin activates AMP-activated protein kinase (AMPK), leading to downregulation of the mTOR pathway that is crucial to tumor cell metabolism. I would like to mention another possible mechanism. In a recent study [2], it was demonstrated that activating KRAS mutation imposes an embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Metformin inhibits KRAS signaling through mislocalization of KRAS from the plasma membrane to the cytoplasm [3], and, interestingly, in other studies [3,4], this anti-diabetic agent was most effective against tumors with activating mutations in KRAS. KRAS mutations are found in 3050% of patients with sporadic colorectal cancer [5] and, in clinical practice,

KRAS mutation testing permits the selection of individuals (those with RAS wild-type tumors) who might benet from agents that target the epidermal growth factor receptor, as cetuximab. It would also be interesting to know whether metformin together with conventional chemotherapy might have a role in treatment of a subgroup of patients with colorectal cancer.

Conict of interest

The authors state that they have no conicts of interest.

References

[1] Rokkas T, Portincasa P. Colon neoplasia in patients with type 2 diabetes on metformin: a meta-analysis. Eur J Intern Med 2016;33:606. [2] Le Rolle AF, Chiu TK, Zeng Z, et al. Oncogenic KRAS activates an embryonic stem cell- like program in human colon cancer initiation. Oncotarget 2016;7:215974. [3] Iglesias DA, Yates MS, van der Hoeven, et al. Another surprise from metformin: novel mechanism of action via K-ras inuences endometrial cancer response to therapy. Mol Cancer Ther 2013;12:284756. [4] Ma Y, Guo FC, Wang W, Shi HS, Li D, Wang YS. K-ras gene mutation as a predictor of cancer cell responsiveness to metformin. Mol Med Rep 2013;8:7638. [5] Watson R, Liu TC, Ruzinova MB. High frequency of KRAS mutation in early onset colorectal adenocarcinoma: implications for pathogenesis. Hum Pathol 2016. http://dx.doi.org/10.1016/ j.humpath.2016.06.010 .

Francisco José Fernández-Fernández Department of Internal Medicine, Hospital Arquitecto Marcide, Complejo Hospitalario Universitario de Ferrol, Ferrol 15405, Spain E-mail address: fjf.fernandez2@gmail.com.

26 August 2016 Available online xxxx

0953-6205/© 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.