- Email: [email protected]
Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells
Medical Hypotheses xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells Jie Tian, Ke Rui, Shengjun Wang ⇑ Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
a r t i c l e
i n f o
Article history: Received 31 December 2013 Accepted 1 May 2014 Available online xxxx
a b s t r a c t Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play an essential role in tumor-associated immunosuppression, which hampers effective immunotherapeutic approaches. MicroRNAs (miRNAs) are short noncoding RNAs that negatively regulate target gene expression at the posttranscriptional level. miRNAs are involved in regulating cell proliferation, differentiation and maturation, and abnormal expression and function of miRNAs are recognized in various human diseases. Accumulating evidence shows that various miRNAs modulate the development and differentiation of myeloid cells, which implies their possible role in the differentiation of MDSCs into mature myeloid cells. Our recent studies have found that the classical myeloid differentiation related gene runt-related transcription factor 1 (Runx1) and target nuclear factor 1/A (NFI-A) are modulated during the differentiation and maturation of MDSCs while six miRNAs are found to possibly regulate these two targets by miRNA array analysis. Thus, we hypothesize that the predicted miRNAs may modulate the target genes to regulate the differentiation and maturation of MDSCs. Further studies will provide a novel potential approach for tumor immunotherapy. Ó 2014 Published by Elsevier Ltd.
Introduction Tumor-induced immunosuppression is one of the essential mechanisms of tumor escape. A variety of different cells contribute to tumor-elicited immune suppression, including regulatory T cells [1], type 2 NKT cells [2], tumor associated macrophages [3] and myeloid-derived suppressor cells (MDSCs). Increasing evidence indicates that MDSCs are one of the major elements of immunosuppressive network responsible for T cell defective response in cancer. MDSCs are a heterogeneous group of myeloid cells consisting of immature macrophages, DCs, granulocytes and myeloid cells at earlier stages of differentiation [4–7]. In mice, MDSCs express both CD11b and Gr-1 (constituted by Ly6G and Ly6C) (2). Two major subsets of MDSCs are now identified by the expression of Ly6G and Ly6C epitopes: granulocytic MDSCs (CD11b+Ly6G+ Ly6Clow) and monocytic MDSCs (CD11b+Ly6GLy6Chi) [6,8]. In healthy humans, MDSCs are generated in the bone marrow and then differentiate into mature myeloid cells, such as DCs, macrophages and granulocytes. However, in pathological conditions, the differentiation of MDSCs is blocked, leading to the expansion ⇑ Corresponding author. Address: Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu Province, China. Tel.: +86 511 8503 8965; fax: +86 8503 8483. E-mail address: [email protected] (S. Wang).
of this population [6]. MDSCs have been shown to accumulate in tumor-bearing mice and patients as tumor burden increases, which are found to expand in the peripheral lymphoid organs and constitute a majority of tumor infiltrating cells. MDSCs exhibit potent capacity of inhibiting the immune responses of CD4+ T cells, CD8+ T cells and NK cells, leading to tumor-related immune suppression [9,10]. Moreover, MDSCs are reported to induce the expansion of Treg cells [11–13]. Recent studies have revealed that repressor MDSC of tumor-bearing mice show up-regulated expression of arginase, NO synthase and reactive oxygen species (ROS), which suppress T-cell proliferation and lead to enhanced tumor progression [8,14,15]. In addition, Saleem et al. found that MDSCs expressed histamine receptor 1 (HR1) and histamine enhanced MDSC survival and expansion [16]. Due to suppressive cellinduced immunosuppressive microenvironment coupled with T-cell non-responsiveness, immunotherapies based on activation of immune system often show reduced efficacy unless the immune suppression is attenuated. Therefore, elimination of MDSCs may significantly improve anti-tumor immune responses and elicit an effective antitumor immunotherapy. MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs (20–23 nucleotides) that play essential roles in regulating gene expression at the post-transcriptional level. miRNAs bind to the complementary sequence in the 30 un-translated region (30 UTR) of target mRNAs to mediate post-transcriptional gene
http://dx.doi.org/10.1016/j.mehy.2014.05.006 0306-9877/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Tian J et al. Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.006
2
J. Tian et al. / Medical Hypotheses xxx (2014) xxx–xxx
repression by destabilizing target transcripts or inhibiting protein translation. miRNAs have been shown to regulate various biological processes, including the differentiation, maturation, function of immune cells and maintenance of immune homeostasis. The expression and function of miRNAs are critical for the maintenance of the cellular homeostasis and the development of various physiological systems [17–21]. Since miRNAs act as critical regulators in a variety of biological processes, extensive studies on miRNA have characterized both abnormal expression and function of miRNAs in a wide range of human diseases including cancer, autoimmune diseases, chronic inflammatory and metabolic diseases [22–25]. miRNAs regulate MDSCs function MDSCs exert strong immunosuppressive properties via the down-regulation of immune responses. However, the molecular mechanisms involved in the expansion, function and accumulation of MDSCs are largely unclear. Emerging evidence suggests that miRNAs play a key regulatory role in MDSC development, expansion and function. It has been reported that both miR-17-5p and miR-20a could alleviate the suppressive potential of MDSCs in vitro and in vivo. Transfection of miR-17-5p or miR-20a into MDSCs remarkably reduces the production of reactive oxygen species (ROS) and H2O2, which are modulated by STAT3 activation. In addition, MDSCs transfected with miR-17-5p or miR-20a are less able to suppress antigen-specific CD4 and CD8 T cell responses. All these data suggest their potential application in immunotherapy against various diseases, especially cancer [26]. Liu et al. reported that miR-494 was dramatically induced by tumor-derived factors and played an essential role in regulating the antiimmunitary activity of MDSCs in promotion of tumor development [27]. miR-494 activates the PI3K/Akt pathway by targeting phosphatase and tensin homolog (PTEN), thus enhancing the infiltration of MDSCs into tumor tissue and promoting tumor invasion and metastasis via up-regulating the expression of MMPs. Knockdown of miR-494 in vivo inhibited MDSC accumulation and suppressive capacity, and reduced the tumor progression. In addition, TGF-b1 was found to be the main tumor derived factor responsible for the up-regulation of miR-494 in MDSCs. The data reveals that TGF-b1-induced miR-494 expression in MDSCs plays a critical role in modulating the accumulation and functions of MDSCs, which facilitate the exploration of potential targets for therapeutic intervention. The role of miR-223, one of the first identified miRNAs related to myeloid development in myeloid cell expansion and differentiation has been widely studied both in vitro and in vivo. Decreased miR-223 expression has been detected in MDSCs from tumor-bearing mice while the myeloid enhancer factor 2C (MEF2C), the target of miR-223, is up-regulated and promotes myeloid progenitor proliferation and survival. In the presence of prostaglandin E2, miR-223 remarkably inhibits the differentiation of bone marrow cells (BMCs) into MDSCs by targeting MEF2C, which promotes the accumulation of MDSCs. In tumor-bearing mice, up-regulation of miR-223 suppresses MDSC accumulation whereas MEF2C increases the number of MDSCs. Collectively, miR-223 suppresses BMCs differentiation into tumor-induced MDSCs, implying a crucial role for miR-223 in tumor-induced the differentiation and accumulation of MDSC [28–30]. Involvement of miRNAs in the development of myeloid cells miRNAs cloned from mouse BMCs are differentially expressed in various hematopoietic lineages, suggesting their involvement in regulating hematopoietic lineage differentiation [31]. Accumulating data have suggested that miRNAs play critical roles in regulating lineage commitment, myeloid cell differentiation,
expansion, and maturation [21,29,32,33]. For instance, miR-29a, miR-21 and miR-196b participate in myeloid progenitor expansion [34,35]; Deletion of miR-146a in mice results in myeloid progenitor expansion with defective maturation of immature myeloid cells. miRNAs can regulate myeloid lineage development and differentiation by targeting proteins, such as transcription factors involved in cell differentiation and survival. For example, miR223 and miR-424 down-regulate the target nuclear factor 1/A (NFI-A) and promote the myeloid progenitor differentiation into mature myeloid cells. NFI-A counteracts the differentiation of both granulocytes and monocytes, thus its downregulation is crucial for the proceeding of myelopoiesis [28,36–38]. In addition, miR-17-5p, miR-20a and miR-106a are found to inhibit monocytic differentiation and maturation of human CD34+ hematopoietic progenitor cells. miR-17-5p, miR-20a and miR-106a levels are negatively correlated with the expression of transcription factor runt-related transcription factor 1 (Runx1) and up-regulation of Runx1 promotes human monocyte differentiation and maturation. Accordingly, transfection with miRNA 17-5p-20a-106a suppresses Runx1 expression, reduces M-CSF receptor level, thus leading to enhanced blast proliferation and inhibition of monocytic differentiation and maturation [39]. Hypothesis Since compelling evidence indicates that MDSC is one of the major elements in tumor-associated immune suppression, elimination of MDSCs may remarkably improve anti-tumor immune responses and elicit an effective cancer immunotherapy. Promotion of MDSCs differentiation into mature myeloid cells without suppressive capacity might be considered as a promising approach in cancer immunotherapy. Although miRNAs are known to regulate myeloid lineage differentiation and maturation, the molecular mechanisms underlying the function of miRNAs in regulating the differentiation of MDSC into mature myeloid cells are poorly understood. Thus, our objective is to explore the possible miRNAs related to the differentiation and maturation of MDSCs. Our recent studies have found that two myeloid cell differentiation related factors, Runx1 and NFI-A are modulated during the differentiation of MDSCs. We have demonstrated that Runx1 is up-regulated while the level of NFI-A is reduced during the cell maturation, which suggests Runx1 and NFI-A are extremely associated with the differentiation of MDSCs. Having confirmed the function of Runx1 and NFI-A in MDSCs, we further examined the possible miRNAs targeting these two genes respectively. We analyzed various miRNAs expression during the differentiation of MDSCs by microRNA array, and then selected the changed miRNAs. Furthermore, we used the predictive software (TargetScan, PicTar and miRanda) to predict and select the possible miRNAs target Runx1 or NFI-A in those changed miRNAs. Finally, we found that the possible miRNAs target Runx1 might be miR-181b/d, miR-9, miR-30b, and miR-21, miR-27b might target NFI-A. Therefore, our hypothesis is some of these miRNAs might target Runx1 or NFI-A to modulate the differentiation of MDSCs, down-regulation the accumulation and function of MDSCs in tumor-bearing host, which will be potential targets for cancer treatment. Thus, our future studies aim to identify the target relationship between miRNAs and target genes, determine the effect of six miRNAs in regulating MDSCs maturation, investigate the effect of miRNAs in vitro and in vivo, and validate the potential of miRNAs for immunotherapy in cancers. Funding This work was supported by the National Natural Science Foundation of China (Grant No. 31170849), Specialized Research
Please cite this article in press as: Tian J et al. Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.006
J. Tian et al. / Medical Hypotheses xxx (2014) xxx–xxx
Fund for the Doctoral Program of Higher Education (Grant No. 20133227110008), Health Department Foundation of Jiangsu Province (Grant No. Z201312), Graduate Student Research and Innovation Program of Jiangsu Province (Grant Nos. CXZZ12_0710, CXZZ13_0700), Jiangsu Province ‘‘333’’ Project and ‘‘Qinglan’’ Project, and Top Talent Program of Jiangsu University.
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Conflicts of interest statement The authors have no financial conflicts of interest. References
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Please cite this article in press as: Tian J et al. Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.006
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells Jie Tian, Ke Rui, Shengjun Wang ⇑ Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
a r t i c l e
i n f o
Article history: Received 31 December 2013 Accepted 1 May 2014 Available online xxxx
a b s t r a c t Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play an essential role in tumor-associated immunosuppression, which hampers effective immunotherapeutic approaches. MicroRNAs (miRNAs) are short noncoding RNAs that negatively regulate target gene expression at the posttranscriptional level. miRNAs are involved in regulating cell proliferation, differentiation and maturation, and abnormal expression and function of miRNAs are recognized in various human diseases. Accumulating evidence shows that various miRNAs modulate the development and differentiation of myeloid cells, which implies their possible role in the differentiation of MDSCs into mature myeloid cells. Our recent studies have found that the classical myeloid differentiation related gene runt-related transcription factor 1 (Runx1) and target nuclear factor 1/A (NFI-A) are modulated during the differentiation and maturation of MDSCs while six miRNAs are found to possibly regulate these two targets by miRNA array analysis. Thus, we hypothesize that the predicted miRNAs may modulate the target genes to regulate the differentiation and maturation of MDSCs. Further studies will provide a novel potential approach for tumor immunotherapy. Ó 2014 Published by Elsevier Ltd.
Introduction Tumor-induced immunosuppression is one of the essential mechanisms of tumor escape. A variety of different cells contribute to tumor-elicited immune suppression, including regulatory T cells [1], type 2 NKT cells [2], tumor associated macrophages [3] and myeloid-derived suppressor cells (MDSCs). Increasing evidence indicates that MDSCs are one of the major elements of immunosuppressive network responsible for T cell defective response in cancer. MDSCs are a heterogeneous group of myeloid cells consisting of immature macrophages, DCs, granulocytes and myeloid cells at earlier stages of differentiation [4–7]. In mice, MDSCs express both CD11b and Gr-1 (constituted by Ly6G and Ly6C) (2). Two major subsets of MDSCs are now identified by the expression of Ly6G and Ly6C epitopes: granulocytic MDSCs (CD11b+Ly6G+ Ly6Clow) and monocytic MDSCs (CD11b+Ly6GLy6Chi) [6,8]. In healthy humans, MDSCs are generated in the bone marrow and then differentiate into mature myeloid cells, such as DCs, macrophages and granulocytes. However, in pathological conditions, the differentiation of MDSCs is blocked, leading to the expansion ⇑ Corresponding author. Address: Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu Province, China. Tel.: +86 511 8503 8965; fax: +86 8503 8483. E-mail address: [email protected] (S. Wang).
of this population [6]. MDSCs have been shown to accumulate in tumor-bearing mice and patients as tumor burden increases, which are found to expand in the peripheral lymphoid organs and constitute a majority of tumor infiltrating cells. MDSCs exhibit potent capacity of inhibiting the immune responses of CD4+ T cells, CD8+ T cells and NK cells, leading to tumor-related immune suppression [9,10]. Moreover, MDSCs are reported to induce the expansion of Treg cells [11–13]. Recent studies have revealed that repressor MDSC of tumor-bearing mice show up-regulated expression of arginase, NO synthase and reactive oxygen species (ROS), which suppress T-cell proliferation and lead to enhanced tumor progression [8,14,15]. In addition, Saleem et al. found that MDSCs expressed histamine receptor 1 (HR1) and histamine enhanced MDSC survival and expansion [16]. Due to suppressive cellinduced immunosuppressive microenvironment coupled with T-cell non-responsiveness, immunotherapies based on activation of immune system often show reduced efficacy unless the immune suppression is attenuated. Therefore, elimination of MDSCs may significantly improve anti-tumor immune responses and elicit an effective antitumor immunotherapy. MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs (20–23 nucleotides) that play essential roles in regulating gene expression at the post-transcriptional level. miRNAs bind to the complementary sequence in the 30 un-translated region (30 UTR) of target mRNAs to mediate post-transcriptional gene
http://dx.doi.org/10.1016/j.mehy.2014.05.006 0306-9877/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Tian J et al. Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.006
2
J. Tian et al. / Medical Hypotheses xxx (2014) xxx–xxx
repression by destabilizing target transcripts or inhibiting protein translation. miRNAs have been shown to regulate various biological processes, including the differentiation, maturation, function of immune cells and maintenance of immune homeostasis. The expression and function of miRNAs are critical for the maintenance of the cellular homeostasis and the development of various physiological systems [17–21]. Since miRNAs act as critical regulators in a variety of biological processes, extensive studies on miRNA have characterized both abnormal expression and function of miRNAs in a wide range of human diseases including cancer, autoimmune diseases, chronic inflammatory and metabolic diseases [22–25]. miRNAs regulate MDSCs function MDSCs exert strong immunosuppressive properties via the down-regulation of immune responses. However, the molecular mechanisms involved in the expansion, function and accumulation of MDSCs are largely unclear. Emerging evidence suggests that miRNAs play a key regulatory role in MDSC development, expansion and function. It has been reported that both miR-17-5p and miR-20a could alleviate the suppressive potential of MDSCs in vitro and in vivo. Transfection of miR-17-5p or miR-20a into MDSCs remarkably reduces the production of reactive oxygen species (ROS) and H2O2, which are modulated by STAT3 activation. In addition, MDSCs transfected with miR-17-5p or miR-20a are less able to suppress antigen-specific CD4 and CD8 T cell responses. All these data suggest their potential application in immunotherapy against various diseases, especially cancer [26]. Liu et al. reported that miR-494 was dramatically induced by tumor-derived factors and played an essential role in regulating the antiimmunitary activity of MDSCs in promotion of tumor development [27]. miR-494 activates the PI3K/Akt pathway by targeting phosphatase and tensin homolog (PTEN), thus enhancing the infiltration of MDSCs into tumor tissue and promoting tumor invasion and metastasis via up-regulating the expression of MMPs. Knockdown of miR-494 in vivo inhibited MDSC accumulation and suppressive capacity, and reduced the tumor progression. In addition, TGF-b1 was found to be the main tumor derived factor responsible for the up-regulation of miR-494 in MDSCs. The data reveals that TGF-b1-induced miR-494 expression in MDSCs plays a critical role in modulating the accumulation and functions of MDSCs, which facilitate the exploration of potential targets for therapeutic intervention. The role of miR-223, one of the first identified miRNAs related to myeloid development in myeloid cell expansion and differentiation has been widely studied both in vitro and in vivo. Decreased miR-223 expression has been detected in MDSCs from tumor-bearing mice while the myeloid enhancer factor 2C (MEF2C), the target of miR-223, is up-regulated and promotes myeloid progenitor proliferation and survival. In the presence of prostaglandin E2, miR-223 remarkably inhibits the differentiation of bone marrow cells (BMCs) into MDSCs by targeting MEF2C, which promotes the accumulation of MDSCs. In tumor-bearing mice, up-regulation of miR-223 suppresses MDSC accumulation whereas MEF2C increases the number of MDSCs. Collectively, miR-223 suppresses BMCs differentiation into tumor-induced MDSCs, implying a crucial role for miR-223 in tumor-induced the differentiation and accumulation of MDSC [28–30]. Involvement of miRNAs in the development of myeloid cells miRNAs cloned from mouse BMCs are differentially expressed in various hematopoietic lineages, suggesting their involvement in regulating hematopoietic lineage differentiation [31]. Accumulating data have suggested that miRNAs play critical roles in regulating lineage commitment, myeloid cell differentiation,
expansion, and maturation [21,29,32,33]. For instance, miR-29a, miR-21 and miR-196b participate in myeloid progenitor expansion [34,35]; Deletion of miR-146a in mice results in myeloid progenitor expansion with defective maturation of immature myeloid cells. miRNAs can regulate myeloid lineage development and differentiation by targeting proteins, such as transcription factors involved in cell differentiation and survival. For example, miR223 and miR-424 down-regulate the target nuclear factor 1/A (NFI-A) and promote the myeloid progenitor differentiation into mature myeloid cells. NFI-A counteracts the differentiation of both granulocytes and monocytes, thus its downregulation is crucial for the proceeding of myelopoiesis [28,36–38]. In addition, miR-17-5p, miR-20a and miR-106a are found to inhibit monocytic differentiation and maturation of human CD34+ hematopoietic progenitor cells. miR-17-5p, miR-20a and miR-106a levels are negatively correlated with the expression of transcription factor runt-related transcription factor 1 (Runx1) and up-regulation of Runx1 promotes human monocyte differentiation and maturation. Accordingly, transfection with miRNA 17-5p-20a-106a suppresses Runx1 expression, reduces M-CSF receptor level, thus leading to enhanced blast proliferation and inhibition of monocytic differentiation and maturation [39]. Hypothesis Since compelling evidence indicates that MDSC is one of the major elements in tumor-associated immune suppression, elimination of MDSCs may remarkably improve anti-tumor immune responses and elicit an effective cancer immunotherapy. Promotion of MDSCs differentiation into mature myeloid cells without suppressive capacity might be considered as a promising approach in cancer immunotherapy. Although miRNAs are known to regulate myeloid lineage differentiation and maturation, the molecular mechanisms underlying the function of miRNAs in regulating the differentiation of MDSC into mature myeloid cells are poorly understood. Thus, our objective is to explore the possible miRNAs related to the differentiation and maturation of MDSCs. Our recent studies have found that two myeloid cell differentiation related factors, Runx1 and NFI-A are modulated during the differentiation of MDSCs. We have demonstrated that Runx1 is up-regulated while the level of NFI-A is reduced during the cell maturation, which suggests Runx1 and NFI-A are extremely associated with the differentiation of MDSCs. Having confirmed the function of Runx1 and NFI-A in MDSCs, we further examined the possible miRNAs targeting these two genes respectively. We analyzed various miRNAs expression during the differentiation of MDSCs by microRNA array, and then selected the changed miRNAs. Furthermore, we used the predictive software (TargetScan, PicTar and miRanda) to predict and select the possible miRNAs target Runx1 or NFI-A in those changed miRNAs. Finally, we found that the possible miRNAs target Runx1 might be miR-181b/d, miR-9, miR-30b, and miR-21, miR-27b might target NFI-A. Therefore, our hypothesis is some of these miRNAs might target Runx1 or NFI-A to modulate the differentiation of MDSCs, down-regulation the accumulation and function of MDSCs in tumor-bearing host, which will be potential targets for cancer treatment. Thus, our future studies aim to identify the target relationship between miRNAs and target genes, determine the effect of six miRNAs in regulating MDSCs maturation, investigate the effect of miRNAs in vitro and in vivo, and validate the potential of miRNAs for immunotherapy in cancers. Funding This work was supported by the National Natural Science Foundation of China (Grant No. 31170849), Specialized Research
Please cite this article in press as: Tian J et al. Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.006
J. Tian et al. / Medical Hypotheses xxx (2014) xxx–xxx
Fund for the Doctoral Program of Higher Education (Grant No. 20133227110008), Health Department Foundation of Jiangsu Province (Grant No. Z201312), Graduate Student Research and Innovation Program of Jiangsu Province (Grant Nos. CXZZ12_0710, CXZZ13_0700), Jiangsu Province ‘‘333’’ Project and ‘‘Qinglan’’ Project, and Top Talent Program of Jiangsu University.
[17] [18] [19]
[20]
Conflicts of interest statement The authors have no financial conflicts of interest. References
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Please cite this article in press as: Tian J et al. Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.006