Leukemia Research 38 (2014) 1158–1159
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
A paradigm for cybernetics, regulatory circuits and ultra-stability in cancer biology and treatment
Keywords: JAK/STAT pathway STAT3 SOCS1 miR-155 Differentiation therapy Cancer cybernetics Ultra-stability
Cancer is a consequence of dysbalances between cell proliferation, cell death and cell differentiation. In addition to anti-proliferative and cytotoxic therapy, differentiation inducing therapy can correct these dysbalances. Recent examples of forced differentiation of cancer cells have been described, e.g., for glioblastoma cells [1,2], thyroid carcinoma cells [3], liver cancer cells [4], and sarcoma cells [5]. In the treatment protocols for patients with neuroblastoma and acute promyelocytic leukemia, differentiation induction therapy has been successfully established [6]. In the present issue of Leukemia Research, Xu et al. [7] describe an interesting mechanism for the induction of differentiation of the promyelocytic leukemia cell line HL-60 by the cytoplasmic domain of the leukemia inhibitory factor receptor alpha (LIFR␣-CT3). In the proposed cybernetic model LIFR␣-CT3 increases phosphorylation of STAT3 (signal transducer and activator of transcription 3) which leads to suppression of microRNA-155 (miR-155). As a consequence, the miR-155 target SOCS1 (suppressor of cytokine signaling 1) is up-regulated which in turn suppresses phosphorylated STAT3 (pSTAT3) below the baseline level. Finally, the long-term suppression of pSTAT3 might be responsible for the differentiation of the leukemia cells. This model is probably an interesting paradigm for the importance of regulatory circuits in leukemia biology. At diagnosis, cancer cells have a long history of co-evolution with the immune-system and the supporting stroma of the patient. Lessons from patients receiving tumor-cell contaminated organ transplants indicate that the time from tumor cell insemination to diagnosis can be very long. Very late tumor recurrences also indicate that cancer cells and normal cells can stay for a very long time in a state of co-existence [8,9]. Oncogenes are able to address multiple pathways necessary for cancer cell survival in vivo. For instance, MYC and RAS oncogenes can not only drive cell proliferation but can
DOI of original article: http://dx.doi.org/10.1016/j.leukres.2014.07.004. http://dx.doi.org/10.1016/j.leukres.2014.07.011 0145-2126/© 2014 Elsevier Ltd. All rights reserved.
also impair the immunostimulatory activity of cancer cells [10,11] and modulate activity of invasion-associated metalloproteinases [12]. It seems likely that many oncogenes can only be recognized as oncogenes because they are able to support cancer cell growth and survival at multiple levels. It can be expected that in most cases clinically detectable cancer cells are more or less optimally adapted to the given growth conditions in vivo. This adaptation occurs not necessarily at the cellular level. The heterogeneity of cancer cells in an individual patient can also be a consequence of adaptation and functional compartimentation [13]. Factors and pathways involved in adaptation processes are interesting therapeutic targets. Assuming that cancer cells are optimally adapted to the given environment in vivo or in vitro, it is not surprising that in many cases the inhibition or knock-down of proposed important factors like oncogenes can induce cell cycle arrest, apoptosis or differentiation of the cells. However, rebound effects with increased activity of the inhibited factor after clearance of the inhibitor as well as the activation of compensatory pathways are common observations (e.g. [14,15]). Rebound effects are consequences of cybernetic feedback loops that might also be responsible for the development of resistance against selective pathway-inhibitors or differentiation inducing agents. Interestingly, the model suggested by Xu et al. [7] for the differentiation of HL-60 cells by LIFR␣-CT3 implies a complex feedback mechanism for prolonged down-modulation of STAT3 after transient hyper-activation. Under steady state conditions, the expression levels and activities of the oncogene STAT3, the oncogenic microRNA mIR-155 and the tumor suppressor gene SOCS1 are obviously balanced, allowing STAT3 to fulfill its oncogenic functions. A short hyper-activation of STAT3 activates the negative feedback loop by suppression of miR-155 which finally leads to suppression of STAT3. It seems paradox that the (transient) activation of an oncogene can inhibit tumor cell growth. However, similar observations have recently been published for the oncogene SYK (spleen tyrosine kinase) [16]. In this case, activation of the oncogene in B cells induces up-regulation of BLIMP1 (B lymphocyte-induced maturation protein 1) and subsequent differentiation into plasma cells. Obviously the STAT3/miR-155/SOCS1/STAT3 inhibition pathway requires an intact feedback loop. Especially SOCS1 is often inactivated in cancer cells by mutations or down-regulation [17] suggesting that inactivation of this tumor suppressor facilitates cancer cell proliferation and survival in vivo. In cells with inactivated SOCS1 the described feedback loop cannot work and in this case one would expect lower or absent differentiation inducing activity of LIFR␣-CT3. SOCS1 has multiple interaction partners and
Editorial / Leukemia Research 38 (2014) 1158–1159
is involved in multiple signaling pathways. Whether other interaction partners might contribute to LIFR␣-CT3-induced growth inhibition and differentiation requires further investigations. At the single cell level, induction of apoptosis or terminal differentiation can permanently stop cellular reproduction. The total population of cancer cells in a patient (or in a cell culture) can respond by selection of cell clones that are resistant against the used apoptosis/differentiation inductor. At the cellular level, inhibition of a pathway that cannot be resolved by activation of feedback loops can force the activation of compensating pathways that allow cell survival despite ongoing inhibition of the first pathway. Referring to Ashby [18] this can be called a form of ultra-stability. Ultra-stability is the ability of a system to acquire a new state of equilibrium if the environmental parameters have changed in a way not allowing the return to the old state of equilibrium. Ultra-stability is a typical feature of biological systems. In the model proposed by Xu et al. [7] the differentiated tumor cell can also be considered as a cell that has reached a new equilibrium. During the absence of pSTAT3 signaling (as long as the inhibition of SOCS1 by miR-155 has not been re-established) the cell cannot return to the old equilibrium. In the new state of equilibrium new regulatory circuits have been established and inhibit the reversion into the old state of equilibrium (i.e. cell proliferation). The differentiated phenotype is only one state of equilibrium. Unfortunately, cancer cells often can find other equilibria by usage of alternative or compensatory pathways that allow proliferation despite inhibition of one pathway. Direct inhibition of STAT3 expression or function might be a more direct way of targeting this pathway in cancer cells. However, further analysis of the involved regulatory circuit and interacting pathways during LIFR␣-CT3-induced differentiation might allow further elucidation of the basic cybernetic behavior of leukemia cells.
[5]
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
[17] [18]
Conflict of interest The author declares that he has no conflict of interest. References [1] Yang C, Lei D, Ouyang W, Ren J, Li H, Hu J, et al. Conditioned media from human adipose tissue-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells efficiently induced the apoptosis and differentiation in human glioma cell lines in vitro. Biomed Res Int 2014;2014:109389. [2] Kang TW, Choi SW, Yang SR, Shin TH, Kim HS, Yu KR, et al. Growth arrest and forced differentiation of human primary glioblastoma multiforme by a novel small molecule. Sci Rep 2014;4:5546. [3] Haghpanah V, Malehmir M, Larijani B, Ahmadian S, Alimoghaddam K, Heshmat R, et al. The beneficial effects of valproic acid in thyroid cancer are mediated through promoting redifferentiation and reducing stemness level: an in vitro study. J Thyroid Res 2014;2014:218763. [4] You N, Zheng L, Liu W, Zhong X, Wang W, Li J. Proliferation inhibition and differentiation induction of hepatic cancer stem cells by knockdown of BC047440:
1159
a potential therapeutic target of stem cell treatment for hepatocellular carcinoma. Oncol Rep 2014;31:1911–20. Cain JE, McCaw A, Jayasekara WS, Rossello FJ, Marini KD, Irving AT, et al. Sustained low-dose treatment with the histone deacetylase inhibitor LBH589 induces terminal differentiation of osteosarcoma cells. Sarcoma 2013;2013:608964. Masetti R, Biagi C, Zama D, Vendemini F, Martoni A, Morello W, et al. Retinoids in pediatric onco-hematology: the model of acute promyelocytic leukemia and neuroblastoma. Adv Ther 2012;29:747–62. Xu S, Xu Z, Liu B, Sun Q, Yang L, Wang J, et al. LIFR␣-CT3 induces differentiation of a human acute myelogenous leukemia cell line HL-60 by suppressing miR-155 expression through the JAK/STAT pathway. Leuk Res 2014;38:1237–44. Xiao D, Craig JC, Chapman JR, Dominguez-Gil B, Tong A, Wong G. Donor cancer transmission in kidney transplantation: a systematic review. Am J Transplant 2013;13:2645–52. Strauss DC, Thomas JM. Transmission of donor melanoma by organ transplantation. Lancet Oncol 2010;11:790–6. Seliger B, Harders C, Wollscheid U, Staege MS, Reske-Kunz AB, Huber C. Suppression of MHC class I antigens in oncogenic transformants: association with decreased recognition by cytotoxic T lymphocytes. Exp Hematol 1996;24:1275–9. Staege MS, Lee SP, Frisan T, Mautner J, Scholz S, Pajic A, et al. MYC overexpression imposes a nonimmunogenic phenotype on Epstein-Barr virus-infected B cells. Proc Natl Acad Sci USA 2002;99:4550–5. Takahashi C, Sheng Z, Horan TP, Kitayama H, Maki M, Hitomi K, et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci USA 1998;95:13221–6. Grunewald TG, Herbst SM, Heinze J, Burdach S. Understanding tumor heterogeneity as functional compartments – superorganisms revisited. J Transl Med 2011;9:79. Wang K, Bodempudi V, Liu Z, Borrego-Diaz E, Yamoutpoor F, Meyer A, et al. Inhibition of mesothelin as a novel strategy for targeting cancer cells. PLoS One 2012;7:e33214. Johnson FM, Saigal B, Tran H, Donato NJ. Abrogation of signal transducer and activator of transcription 3 reactivation after Src kinase inhibition results in synergistic antitumor effects. Clin Cancer Res 2007;13:4233–44. Hug E, Hobeika E, Reth M, Jumaa H. Inducible expression of hyperactive Syk in B cells activates Blimp-1-dependent terminal differentiation. Oncogene 2014;33:3730–41. Sasi W, Sharma AK, Mokbel K. The role of suppressors of cytokine signalling in human neoplasms. Mol Biol Int 2014;2014:630797. Ashby WR. Design for a brain. 2nd ed. New York: John Wiley & Sons; 1960.
Martin S. Staege ∗ Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Halle, Germany ∗ Correspondence
to: Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06097 Halle, Germany. Tel.: +49 345 557 7280; fax: +49 345 557 7275. E-mail address: [email protected] 25 July 2014 Available online 4 August 2014
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
A paradigm for cybernetics, regulatory circuits and ultra-stability in cancer biology and treatment
Keywords: JAK/STAT pathway STAT3 SOCS1 miR-155 Differentiation therapy Cancer cybernetics Ultra-stability
Cancer is a consequence of dysbalances between cell proliferation, cell death and cell differentiation. In addition to anti-proliferative and cytotoxic therapy, differentiation inducing therapy can correct these dysbalances. Recent examples of forced differentiation of cancer cells have been described, e.g., for glioblastoma cells [1,2], thyroid carcinoma cells [3], liver cancer cells [4], and sarcoma cells [5]. In the treatment protocols for patients with neuroblastoma and acute promyelocytic leukemia, differentiation induction therapy has been successfully established [6]. In the present issue of Leukemia Research, Xu et al. [7] describe an interesting mechanism for the induction of differentiation of the promyelocytic leukemia cell line HL-60 by the cytoplasmic domain of the leukemia inhibitory factor receptor alpha (LIFR␣-CT3). In the proposed cybernetic model LIFR␣-CT3 increases phosphorylation of STAT3 (signal transducer and activator of transcription 3) which leads to suppression of microRNA-155 (miR-155). As a consequence, the miR-155 target SOCS1 (suppressor of cytokine signaling 1) is up-regulated which in turn suppresses phosphorylated STAT3 (pSTAT3) below the baseline level. Finally, the long-term suppression of pSTAT3 might be responsible for the differentiation of the leukemia cells. This model is probably an interesting paradigm for the importance of regulatory circuits in leukemia biology. At diagnosis, cancer cells have a long history of co-evolution with the immune-system and the supporting stroma of the patient. Lessons from patients receiving tumor-cell contaminated organ transplants indicate that the time from tumor cell insemination to diagnosis can be very long. Very late tumor recurrences also indicate that cancer cells and normal cells can stay for a very long time in a state of co-existence [8,9]. Oncogenes are able to address multiple pathways necessary for cancer cell survival in vivo. For instance, MYC and RAS oncogenes can not only drive cell proliferation but can
DOI of original article: http://dx.doi.org/10.1016/j.leukres.2014.07.004. http://dx.doi.org/10.1016/j.leukres.2014.07.011 0145-2126/© 2014 Elsevier Ltd. All rights reserved.
also impair the immunostimulatory activity of cancer cells [10,11] and modulate activity of invasion-associated metalloproteinases [12]. It seems likely that many oncogenes can only be recognized as oncogenes because they are able to support cancer cell growth and survival at multiple levels. It can be expected that in most cases clinically detectable cancer cells are more or less optimally adapted to the given growth conditions in vivo. This adaptation occurs not necessarily at the cellular level. The heterogeneity of cancer cells in an individual patient can also be a consequence of adaptation and functional compartimentation [13]. Factors and pathways involved in adaptation processes are interesting therapeutic targets. Assuming that cancer cells are optimally adapted to the given environment in vivo or in vitro, it is not surprising that in many cases the inhibition or knock-down of proposed important factors like oncogenes can induce cell cycle arrest, apoptosis or differentiation of the cells. However, rebound effects with increased activity of the inhibited factor after clearance of the inhibitor as well as the activation of compensatory pathways are common observations (e.g. [14,15]). Rebound effects are consequences of cybernetic feedback loops that might also be responsible for the development of resistance against selective pathway-inhibitors or differentiation inducing agents. Interestingly, the model suggested by Xu et al. [7] for the differentiation of HL-60 cells by LIFR␣-CT3 implies a complex feedback mechanism for prolonged down-modulation of STAT3 after transient hyper-activation. Under steady state conditions, the expression levels and activities of the oncogene STAT3, the oncogenic microRNA mIR-155 and the tumor suppressor gene SOCS1 are obviously balanced, allowing STAT3 to fulfill its oncogenic functions. A short hyper-activation of STAT3 activates the negative feedback loop by suppression of miR-155 which finally leads to suppression of STAT3. It seems paradox that the (transient) activation of an oncogene can inhibit tumor cell growth. However, similar observations have recently been published for the oncogene SYK (spleen tyrosine kinase) [16]. In this case, activation of the oncogene in B cells induces up-regulation of BLIMP1 (B lymphocyte-induced maturation protein 1) and subsequent differentiation into plasma cells. Obviously the STAT3/miR-155/SOCS1/STAT3 inhibition pathway requires an intact feedback loop. Especially SOCS1 is often inactivated in cancer cells by mutations or down-regulation [17] suggesting that inactivation of this tumor suppressor facilitates cancer cell proliferation and survival in vivo. In cells with inactivated SOCS1 the described feedback loop cannot work and in this case one would expect lower or absent differentiation inducing activity of LIFR␣-CT3. SOCS1 has multiple interaction partners and
Editorial / Leukemia Research 38 (2014) 1158–1159
is involved in multiple signaling pathways. Whether other interaction partners might contribute to LIFR␣-CT3-induced growth inhibition and differentiation requires further investigations. At the single cell level, induction of apoptosis or terminal differentiation can permanently stop cellular reproduction. The total population of cancer cells in a patient (or in a cell culture) can respond by selection of cell clones that are resistant against the used apoptosis/differentiation inductor. At the cellular level, inhibition of a pathway that cannot be resolved by activation of feedback loops can force the activation of compensating pathways that allow cell survival despite ongoing inhibition of the first pathway. Referring to Ashby [18] this can be called a form of ultra-stability. Ultra-stability is the ability of a system to acquire a new state of equilibrium if the environmental parameters have changed in a way not allowing the return to the old state of equilibrium. Ultra-stability is a typical feature of biological systems. In the model proposed by Xu et al. [7] the differentiated tumor cell can also be considered as a cell that has reached a new equilibrium. During the absence of pSTAT3 signaling (as long as the inhibition of SOCS1 by miR-155 has not been re-established) the cell cannot return to the old equilibrium. In the new state of equilibrium new regulatory circuits have been established and inhibit the reversion into the old state of equilibrium (i.e. cell proliferation). The differentiated phenotype is only one state of equilibrium. Unfortunately, cancer cells often can find other equilibria by usage of alternative or compensatory pathways that allow proliferation despite inhibition of one pathway. Direct inhibition of STAT3 expression or function might be a more direct way of targeting this pathway in cancer cells. However, further analysis of the involved regulatory circuit and interacting pathways during LIFR␣-CT3-induced differentiation might allow further elucidation of the basic cybernetic behavior of leukemia cells.
[5]
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
[17] [18]
Conflict of interest The author declares that he has no conflict of interest. References [1] Yang C, Lei D, Ouyang W, Ren J, Li H, Hu J, et al. Conditioned media from human adipose tissue-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells efficiently induced the apoptosis and differentiation in human glioma cell lines in vitro. Biomed Res Int 2014;2014:109389. [2] Kang TW, Choi SW, Yang SR, Shin TH, Kim HS, Yu KR, et al. Growth arrest and forced differentiation of human primary glioblastoma multiforme by a novel small molecule. Sci Rep 2014;4:5546. [3] Haghpanah V, Malehmir M, Larijani B, Ahmadian S, Alimoghaddam K, Heshmat R, et al. The beneficial effects of valproic acid in thyroid cancer are mediated through promoting redifferentiation and reducing stemness level: an in vitro study. J Thyroid Res 2014;2014:218763. [4] You N, Zheng L, Liu W, Zhong X, Wang W, Li J. Proliferation inhibition and differentiation induction of hepatic cancer stem cells by knockdown of BC047440:
1159
a potential therapeutic target of stem cell treatment for hepatocellular carcinoma. Oncol Rep 2014;31:1911–20. Cain JE, McCaw A, Jayasekara WS, Rossello FJ, Marini KD, Irving AT, et al. Sustained low-dose treatment with the histone deacetylase inhibitor LBH589 induces terminal differentiation of osteosarcoma cells. Sarcoma 2013;2013:608964. Masetti R, Biagi C, Zama D, Vendemini F, Martoni A, Morello W, et al. Retinoids in pediatric onco-hematology: the model of acute promyelocytic leukemia and neuroblastoma. Adv Ther 2012;29:747–62. Xu S, Xu Z, Liu B, Sun Q, Yang L, Wang J, et al. LIFR␣-CT3 induces differentiation of a human acute myelogenous leukemia cell line HL-60 by suppressing miR-155 expression through the JAK/STAT pathway. Leuk Res 2014;38:1237–44. Xiao D, Craig JC, Chapman JR, Dominguez-Gil B, Tong A, Wong G. Donor cancer transmission in kidney transplantation: a systematic review. Am J Transplant 2013;13:2645–52. Strauss DC, Thomas JM. Transmission of donor melanoma by organ transplantation. Lancet Oncol 2010;11:790–6. Seliger B, Harders C, Wollscheid U, Staege MS, Reske-Kunz AB, Huber C. Suppression of MHC class I antigens in oncogenic transformants: association with decreased recognition by cytotoxic T lymphocytes. Exp Hematol 1996;24:1275–9. Staege MS, Lee SP, Frisan T, Mautner J, Scholz S, Pajic A, et al. MYC overexpression imposes a nonimmunogenic phenotype on Epstein-Barr virus-infected B cells. Proc Natl Acad Sci USA 2002;99:4550–5. Takahashi C, Sheng Z, Horan TP, Kitayama H, Maki M, Hitomi K, et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci USA 1998;95:13221–6. Grunewald TG, Herbst SM, Heinze J, Burdach S. Understanding tumor heterogeneity as functional compartments – superorganisms revisited. J Transl Med 2011;9:79. Wang K, Bodempudi V, Liu Z, Borrego-Diaz E, Yamoutpoor F, Meyer A, et al. Inhibition of mesothelin as a novel strategy for targeting cancer cells. PLoS One 2012;7:e33214. Johnson FM, Saigal B, Tran H, Donato NJ. Abrogation of signal transducer and activator of transcription 3 reactivation after Src kinase inhibition results in synergistic antitumor effects. Clin Cancer Res 2007;13:4233–44. Hug E, Hobeika E, Reth M, Jumaa H. Inducible expression of hyperactive Syk in B cells activates Blimp-1-dependent terminal differentiation. Oncogene 2014;33:3730–41. Sasi W, Sharma AK, Mokbel K. The role of suppressors of cytokine signalling in human neoplasms. Mol Biol Int 2014;2014:630797. Ashby WR. Design for a brain. 2nd ed. New York: John Wiley & Sons; 1960.
Martin S. Staege ∗ Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Halle, Germany ∗ Correspondence
to: Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06097 Halle, Germany. Tel.: +49 345 557 7280; fax: +49 345 557 7275. E-mail address: [email protected] 25 July 2014 Available online 4 August 2014
