Therapeutic potential of the anti-diabetic agent metformin in targeting the skin cancer stem cell diaspora

Authors

  • Anand Reddi,

    Corresponding author
    1. Department of Dermatology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
    2. University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
    • Correspondence: Anand Reddi, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA,

      e-mail: anand.reddi@gmail.com

    Search for more papers by this author
  • Matthew A. Powers,

    1. University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
    Current affiliation:
    1. Department of Ophthalmology, Stanford University, Stanford, CA, USA
    Search for more papers by this author
  • Robert P. Dellavalle

    1. Department of Dermatology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
    2. Department of Dermatology, Denver Veterans Administration Hospital, Denver, CO, USA
    3. Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
    Search for more papers by this author

Abstract

Type II diabetes is associated with increased prevalence of cancer including both melanoma and squamous cell carcinoma (SCC) of the skin. Emerging evidence from epidemiological studies suggest that diabetic patients on metformin have a lower risk of cancer incidence and mortality in a broad range of neoplasms. In both melanoma and SCC, populations of cancer stem cells (CSC) contribute to tumor initiation and metastasis. We propose that metformin constitutes a new class of targeted therapy that acts on the skin CSC diaspora. We posit that metformin selectively and simultaneously targets CSCs of the primary tumor as well as in metastatic niches thereby disrupting the dynamic dispersal of circulating CSCs between the primary tumor and metastatic site. This hypothesis suggests a new concept in dermato-oncology that treatment of type II diabetes and prevention of skin cancer are two sides of the same coin.

Introduction

An emerging area in translational dermatology is the chemoprevention of skin cancer [1]. Chemoprevention, first proposed by Michael Sporn, seeks to identify ‘agents to reverse, suppress or prevent the carcinogenic process,’ from premalignancy to invasive/metastatic cancer, by ‘using physiological mechanisms that do not kill healthy cells’ [2, 3]. We propose a role for the antidiabetes drug metformin as a chemoprevention agent for skin cancer.

Epidemiology of diabetes mellitus and skin cancer

By 2030, an estimated 400 million people worldwide will be afflicted by type II diabetes mellitus [4]. Type II diabetes is associated with increased incidence, prevalence and mortality of different types of cancer [5]. However, an unresolved question in dermato-epidemiology is the association of type II diabetes and skin cancer.

Li et al. [6] resolved the enigmatic relationship between type II diabetes and skin cancer by examining whether the temporal duration of diagnosed diabetes affects cancer prevalence. In a large population-based, cross-sectional study of 25 964 US adults, there was a 2.0-fold higher prevalence in men and a 2.2-fold higher prevalence in women for skin cancer (defined as both melanoma and non-melanoma skin cancer) in patients diagnosed with type II diabetes >15 years ago [6]. The authors adjusted for potential cofounding variables including age, smoking status, alcohol use, obesity and physical status [6]. These data affirm a possible causal link between diabetes (type II) and skin cancer (Appendix S1).

Perspectives from epidemiological studies: metformin is chemoprevention agent

If a causal link exists between type II diabetes and skin cancer, epidemiological studies would reveal that treatment with a hypoglycemic agent such as metformin could reduce skin cancer incidence or mortality. However, to date, no epidemiological studies have studied the effects of metformin on skin cancer incidence and mortality. But, encouragingly, several studies of type II diabetic patients on metformin demonstrated a lower risk of cancer incidence and mortality in a broad range of neoplasms [7-11]. These data suggest that metformin may have a role as a chemoprevention drug and warrant dermato-epidemiological studies to examine skin cancer outcomes (Appendix S1).

Perspectives from basic science: metformin is a potential skin cancer chemoprevention agent?

Evidence of metformin's role as an antitumor agent in both melanoma and cutaneous squamous cell carcinoma (SCC) is emerging [12-16]. Metformin activates AMP-kinase (AMPK) leading to inhibition of the mTOR-signalling pathway [13]. Also, AMPK has been implicated in skin UVB-induced DNA damage [17, 18]. In both melanoma and SCC, metformin inhibited cell proliferation, promoted apoptosis and blocked tumor growth selectively in cancer cells [13, 15, 19] (Figure 1).

Figure 1.

Cell signalling of metformin-mediated chemoprevention in skin cancer. In both melanoma and squamous cell carcinoma (SCC), metformin inhibited cell proliferation, promoted apoptosis and blocked tumor growth by targeting multiple cellular signalling pathways as shown.

In melanoma, AMPK-activation engages the p53 tumor suppressor-signalling axis promoting anticancer signalling [15]. Metformin also has anti-invasive and antimetastatic effects in melanoma by inhibiting epithelial-mesenchymal transition by repressing the transcription factors Slug and Snail [15]. Additionally, metformin decreases Matrix Metalloproteinase activity (molecular regulators of invasiveness and metastasis) [15] (Figure 1). However, metformin can accelerate growth of BRAFV600E mutated melanoma by up-regulation of VEGF [20]. These data suggest that the mutational landscape may contribute to metformin's efficacy.

In SCC, metformin reduced tumor growth by inhibiting the nuclear factor kappa B (NFκB) transcription factor increasing susceptibility to cell death [13]. Metformin also decreased the ERK/p38 MAP kinase signalling as well as AKT signalling (pathways involved in promoting cell proliferation and survival) [13] (Fig. 1).

Hypothesis: metformin targets skin cancer stem cells (CSCs)

Cancer stem cells populations contribute to malignant tumor growth, invasion and metastasis in both melanoma and SCC [21-27]. Massague and colleagues have demonstrated that metastasis is a multidirectional process between primary tumor and metastatic sites [28, 29]. Pienta et al. [30] suggest, ‘Metastasis is not a simple one-way migration, but rather a dynamic dispersal of cells that are inherently linked to the primary tumor’.

Metformin can inhibit the growth of CSCs as well as inhibit the inflammatory response associated with cellular transformation in breast cancer [31-34]. Metformin also potentiates standard chemotherapeutics such as doxorubicin, paclitaxel and cisplatin in breast tumor xenografts [31, 33]. These observations in breast cancer warrant future exploration in both melanoma and SCC.

We propose that metformin constitutes a new class of targeted therapy that acts on the skin CSC diaspora (a term proposed by Pienta et al.). We posit that metformin selectively targets CSCs of the primary tumor as well as in metastatic niches thereby disrupting the ‘dynamic dispersal’ of circulating CSCs between the primary tumor and metastatic site.

Conclusion

Preliminary evidence supports the hypothesis that metformin is a chemoprevention agent for skin cancer. We believe studies should also examine metformin's efficacy to target skin CSC populations intrinsically susceptible to malignancy and metastasis. This hypothesis may result in a new concept in dermato-oncology suggesting that treatment for type II diabetes and prevention of skin cancer are two sides of the same coin.

Author contributions

AR conducted the literature review, formed the hypothesis and wrote the manuscript. MAP created the figure. RPD supervised the study.

Conflict of interest

The authors declare no financial conflict of interest relevant to this article.