Metformin: multi-faceted protection against cancer

Abstract

The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics.

Conflict of interest statement

None to declare.

Figures

Figure 1. Metformin and cancer: From phenomenology to molecular understanding in less than a decade

Since an initial report by Evans et al. [22] revealing that metformin use in people with type 2 diabetes was associated with reduced cancer incidence, the hypothesis that metformin may have clinically relevant preventive and treatment effects in human cancer exploded as an ever-growing research field, as scientists discovered mechanistic connections to pivotal cancer markers and even cancer stem cells. Amazingly, the molecular and clinical breakthroughs in metformin and cancer have taken place during only the past decade.

Figure 2. Metformin: A guardian of EMT and micro(mi)RNA-regulated stemness and cancer progression

A. EMT Induction of the EMT transdifferentiation program in cancer cells results in the acquisition of invasive and metastatic properties. The emergence of CSCs also occurs in part as a result of EMT. In addition, EMT of tumor cells contributes to drug resistance. Figure depicts how metformin's ability to inhibit the EMT transdifferentiation program may represent a therapeutic strategy to clinically overcome chemotherapy refractoriness in CSCs-enriched invasive/metastastic carcinomas. B. Two evolutionary conserved families of miRNAs, let-7 and miR-200, regulate pivotal differentiation processes during development. On the one hand, loss of let-7 in cancer triggers reverse embryogenesis and dedifferentiation phenomena. On the other hand, miR-200 has been identified as a powerful regulator of the EMT process. The figure depicts how deregulation of let-7 and miRNA-200 during carcinogenesis could each contribute to tumor progression, one by controlling let-7 regulated oncofetal genes (LOGs) and, therefore, stem cell maintenance, and the other by regulating EMT and, therefore, the generation of migrating CSCs. Obviously, crosstalk exists between loss of let-7 –that results in reverse embryogenesis and dedifferentiation- and miR-200-regulated EMT –that results in up-regulation of a number of stem cell markers-. Metformin, through its ability to potentiate the expression of let-7a [153] and miR-200 (unpublished observations) and to prevent the overexpression of classical EMT markers such as ZEB, TWIST and SLUG (SNAIL2) [149], may function as an efficient molecular guardian against cancer progression and/or tumor recurrence after treatment.

Figure 3. Metformin-targeted EMT and tumor metabolism: Novel strategy against CSCs

Top. Oncogenic stimuli can either induce senescence or EMT, depending on the cellular and microenvironmental context. Conversely, EMT-inducing transcription factors can simultaneously suppress oncogene-induced senescence (OIS)-like responses and induce an EMT, both phenomena contributing to malignant progression because EMT generates migrating CSCs by directly linking enhanced cellular motility with the maintenance of tumor-initiating (stemness) capacity. Bottom. Rather than constituting a feature of malignancy per se, enhanced aerobic glycolysis and shifts in cellular metabolism away from mitochondrial respiration are intimately linked to malignancy at the level of CSCs. Enhanced glycolysis may play a causal role in the immortality of CSCs by protecting them from the senescent effects of mitochondrial respiration-induced oxidative stress. Metformin's ability to concomitantly attenuate the anti-senescence effects of both the EMT program and the ATP-generating glycolytic metabotype-the Warburg effect- may result in a phenotypic shift that impedes cancer oncogenesis by down-regulating self-renewal and proliferation of CSCs.

Figure 4. Metformin lowered threshold for senescence: Better protection and treatment against cancer

With increasing levels of senescence-inducing stress (e.g., oncogenes, DNA damage, oxidative damage), tumor development goes through three stages namely pre-tumoral, pre-malignant and malignant tumor stages. The stressors normally reach sufficient intensity to trigger senescence only at the pre-malignant tumor stage. If the critical point for triggering senescence can be lowered by metformin by promoting DDR-like signals and/or impeding anti-senescence phenotypes (e.g., EMT, glycolytic metabotypes) in pre-tumoral (top) or tumoral (bottom) tissues, metformin treatment could translate into better protection against cancer (i.e., metformin's cancer prevention modality, top) and could impede progression to advanced and metastatic disease (i.e., metformin's cancer treatment modality, bottom). Our current ability to identify pre-malignant lesions has the potential to allow their early detection and treatment with metformin as a pro-senescence modality. In a neoadjuvant setting, metformin-induced senescence may reduce tumor growth and trigger the immune system to clear senescent cells, contributing to the reduction of tumor burden obtained with traditional chemotherapeutic and radiottherapeutic protocols. Metformin-based pro-senescence approaches may be also advantageous in the adjuvant setting, as it may have the ability to reduce the statistical risk of relapse from occult disease (e.g., residual disease in lymph nodes or systemic micrometastasis) that could arise from remaining quiescent CSCs.