- Email: [email protected]
Is cancer an adaptation of the adult stem cell?
448 direct role for mast cells in skin fibrosis. Clin Exp Allergy 2002;32(2):237–46. [3] Yukselen V, Karaoglu AO, Ozutemiz O, Yenisey C, Tuncyurek M. Ketotifen ameliorates development of fibrosis in alkali burns of the esophagus. Pediatr Surg Int 2004;20(6):429–33 [Epub. 2004 April 24]. [4] Shimane T, Asano K, Suzuki M, Hisamitsu T, Suzaki H. Influence of a macrolide antibiotic, roxithromycin, on mast cell growth and activation in vitro. Mediat Inflamm 2001;10(6):323–32. [5] Fisher DA. A syndrome of acne vulgaris and subclinical dermographic urticaria. Cutis 1991;47(6):429–32.
Correspondence Vahideh Yavari Shiraz University of Medical Sciences School of Medicine Chamran Blvd Shahrak Daneshgahi Eram Daneshpajoohan Street Shiraz, Fars 7194784688 Iran Tel.: +98 917 113 4513 E-mail address: [email protected]
doi:10.1016/j.mehy.2005.09.016
Is cancer an adaptation of the adult stem cell? In spite of different manifestations, etiology, and clinical features of different cancers, they share several principal common characteristics. In almost all instances deregulated cell proliferation and suppressed cell death together provide a minimal underlying platform necessary for neoplastic progression [1]. It is clear that most types of cancer do have external causes. For the industrialized world at the end of the 20th century, the list is headed by tobacco smoke (which is a highly toxic irritant but is not carcinogenic for most experimental animals), various viruses such as hepatitis B and certain papilloma viruses (which are not thought to be mutagenic), various hormonal factors, too many calories in diet, and UV light. Of these, only the last is a conventional mutagen [2]. Killing of cells rather than to cause mutations, are strong stimulators of cell proliferation [1,2]. Both mutagens and carcinogens constitute a stressful environment for cells. The experimental studies so called ‘‘adaptive’’ mutations in bacteria and yeast arising in cells after their exposure to a selective stressful environment, such as medium containing lactose as the only carbon source in experiments with lac-mutants of Escherichia coli reveal possible mechanisms called ‘‘SOS response’’ of this adaptation at the molecular level. It makes a transient limitation of mismatch repair function, point mutations with the participation of special error-prone DNA polymerase, DinB (Pol IV), and gene amplification. These adaptive mutations allows cells to adopt to stress [1]. Normal stem cells have three hallmark features: first, the potential to undergo self-renewal; second, the potential to undergo extensive proliferation; and third, the potential to differentiate into
multiple distinct cell types. Perhaps the most important and useful property of stem cells is that of self renewal. Through this property, striking paralleles can be found between stem cells and cancer cells [3]. Stem cells often persist for long periods of time, instead of dying after short periods of time like may mature cells in highly proliferative tissues [3]. Although stem cells are often the target of genetic events that are necessary or sufficient for malignant transformation, on the other hand, stem cells accumulate few mutations, first because they are defective in DNA repair and tend to do die if they suffer DNA damage, and second because they converse immortal strands and therefore do not accumulate replication errors [4]. Stem cells in G-Zero can be compared to a population of nongrowing bacteria [2]. Given the similarities between adaptive mutations in Escherichia coli and tumorigenesis, it is not unreasonable to expect that further studies of adaptive mutations in stem cells may shed additional light upon the processes by which cancer arise. May be, the cancer is adaptive mechanism of adult stem cell.
References [1] Karpinents TV, Foy BD. Model of the developing tumorigenic phenotype in mammalian cells and the roles of sustained stress and replicative senescence. J Theor Biol 2004;227: 253–64. [2] Cairns J. Mutation and cancer: the antecedents to our studies of adaptive mutation. Genetics 1998;148:1433–40. [3] Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105–11. [4] Cairns J. Somatic stem cells and kinetics of mutagenesis and carcinogenesis. PNAS 2002;99:10567–70.
Correspondence Mesut Tez Ankara Numune Hospital 5th Surgery Clinic Samanpazar, Ankara, Turkey
449 Tel.: +903122153834 E-mail address: [email protected]
doi:10.1016/j.mehy.2005.08.021
Nitric oxide and chronic fatigue syndrome: Are we caring for our patients or are we practicing selfcare? In response to our manuscript published in Medical Hypotheses [1], Dr. M.L. Pall wrote a Letter to the Editor [2] asking for more credit for his own work addressing nitric oxide (NO) in patients with Chronic Fatigue Syndrome (CFS). We would like to thank Dr. Pall for his interest in our work, his careful reading of our manuscripts, and for sharing his view with the readers of Medical Hypotheses. In our response, we will briefly address the major concern raised by Dr. Pall. Second, we will explain that Dr. Pall has misunderstood our proposed theory on intracellular immune deregulation and NO in CFS. Finally and most importantly, we will use the correspondence to plead for more cooperation among CFS researchers around the world, rather than transforming CFS research into a merciless competition among researchers. Dr. Pall indicated that we had failed to adequately reference his previous work. We do acknowledge his work on NO in CFS and related disorders. This is evidenced by the fact that we did reference to his work in each of the manuscripts criticized by Dr. Pall [1,3,4]. At the time we wrote the manuscripts, numerous studies providing scientific evidence supporting a role for NO and oxidative stress in CFS patients had already been published (e.g. [5–7]). Thus, we felt we were no longer obliged to reference to manuscripts hypothesising about the potential role of oxidative stress in CFS. Experimental data are superior to hypotheses. In addition, Dr. Pall challenged the originality of our proposed mechanism for explaining chronic pain in CFS (outlined in [1]). Dr. Pall claimed to have presented the hypothesis in two of his earlier manuscripts, published in 2000 [8] and 2002 [9]. However, the primary intentions of our hypothesis was to
link the observations by Vikman and colleagues (a study published in 2003 [10]) to the current understanding of CFS pathophysiology (Protein Kinase R (PKR) activation, the presence of chronic infections, etc.) and psychopathology (somatization, catastrophizing, activity-avoidance). Thus, it seems unlikely that Dr. Pall had already presented the same hypothesis even before the observations by Vikman et al. [10] were published. Second, it appears that Dr. Pall has misunderstood our proposed theory on intracellular immune deregulation and NO in CFS. He repeatedly stated that we had suggested that ‘‘elevated 37 kDa RNase L activity may generate excessive NO’’ [2]. On the contrary, we had repeatedly suggested that a mechanism distinct from cleaving of the 83 kDa RNase L enzyme may account for the observed increase in NO in CFS patients [1,3,4]. Neither the native RNase L enzyme, nor the cleaving fragments of the native enzyme, are capable of generating increased levels of NO. However, activation of the PKR enzyme leads to phosphorylation of the inhibitor of NF(nuclear factor)-jB (IjB) and consequent NF-jB activation, which in turn causes inducible nitric oxide synthetase (iNOS) expression [11]. iNOS generates increased production of NO by monocytes/macrophages. Fig. 1 on page 252 of [3] provides the reader with a schematically presentation of the distinction between the activation of the PKR enzyme and consequent increased NO availability, and the deregulation of the 20 ,50 -oligoadenylate (2-5A) synthetase/RNase L pathway in CFS. Finally, we would like to make a plead for better cooperation among CFS researchers around the world, rather than acting like competitors. In the past decade, CFS researchers around the world
Correspondence Vahideh Yavari Shiraz University of Medical Sciences School of Medicine Chamran Blvd Shahrak Daneshgahi Eram Daneshpajoohan Street Shiraz, Fars 7194784688 Iran Tel.: +98 917 113 4513 E-mail address: [email protected]
doi:10.1016/j.mehy.2005.09.016
Is cancer an adaptation of the adult stem cell? In spite of different manifestations, etiology, and clinical features of different cancers, they share several principal common characteristics. In almost all instances deregulated cell proliferation and suppressed cell death together provide a minimal underlying platform necessary for neoplastic progression [1]. It is clear that most types of cancer do have external causes. For the industrialized world at the end of the 20th century, the list is headed by tobacco smoke (which is a highly toxic irritant but is not carcinogenic for most experimental animals), various viruses such as hepatitis B and certain papilloma viruses (which are not thought to be mutagenic), various hormonal factors, too many calories in diet, and UV light. Of these, only the last is a conventional mutagen [2]. Killing of cells rather than to cause mutations, are strong stimulators of cell proliferation [1,2]. Both mutagens and carcinogens constitute a stressful environment for cells. The experimental studies so called ‘‘adaptive’’ mutations in bacteria and yeast arising in cells after their exposure to a selective stressful environment, such as medium containing lactose as the only carbon source in experiments with lac-mutants of Escherichia coli reveal possible mechanisms called ‘‘SOS response’’ of this adaptation at the molecular level. It makes a transient limitation of mismatch repair function, point mutations with the participation of special error-prone DNA polymerase, DinB (Pol IV), and gene amplification. These adaptive mutations allows cells to adopt to stress [1]. Normal stem cells have three hallmark features: first, the potential to undergo self-renewal; second, the potential to undergo extensive proliferation; and third, the potential to differentiate into
multiple distinct cell types. Perhaps the most important and useful property of stem cells is that of self renewal. Through this property, striking paralleles can be found between stem cells and cancer cells [3]. Stem cells often persist for long periods of time, instead of dying after short periods of time like may mature cells in highly proliferative tissues [3]. Although stem cells are often the target of genetic events that are necessary or sufficient for malignant transformation, on the other hand, stem cells accumulate few mutations, first because they are defective in DNA repair and tend to do die if they suffer DNA damage, and second because they converse immortal strands and therefore do not accumulate replication errors [4]. Stem cells in G-Zero can be compared to a population of nongrowing bacteria [2]. Given the similarities between adaptive mutations in Escherichia coli and tumorigenesis, it is not unreasonable to expect that further studies of adaptive mutations in stem cells may shed additional light upon the processes by which cancer arise. May be, the cancer is adaptive mechanism of adult stem cell.
References [1] Karpinents TV, Foy BD. Model of the developing tumorigenic phenotype in mammalian cells and the roles of sustained stress and replicative senescence. J Theor Biol 2004;227: 253–64. [2] Cairns J. Mutation and cancer: the antecedents to our studies of adaptive mutation. Genetics 1998;148:1433–40. [3] Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105–11. [4] Cairns J. Somatic stem cells and kinetics of mutagenesis and carcinogenesis. PNAS 2002;99:10567–70.
Correspondence Mesut Tez Ankara Numune Hospital 5th Surgery Clinic Samanpazar, Ankara, Turkey
449 Tel.: +903122153834 E-mail address: [email protected]
doi:10.1016/j.mehy.2005.08.021
Nitric oxide and chronic fatigue syndrome: Are we caring for our patients or are we practicing selfcare? In response to our manuscript published in Medical Hypotheses [1], Dr. M.L. Pall wrote a Letter to the Editor [2] asking for more credit for his own work addressing nitric oxide (NO) in patients with Chronic Fatigue Syndrome (CFS). We would like to thank Dr. Pall for his interest in our work, his careful reading of our manuscripts, and for sharing his view with the readers of Medical Hypotheses. In our response, we will briefly address the major concern raised by Dr. Pall. Second, we will explain that Dr. Pall has misunderstood our proposed theory on intracellular immune deregulation and NO in CFS. Finally and most importantly, we will use the correspondence to plead for more cooperation among CFS researchers around the world, rather than transforming CFS research into a merciless competition among researchers. Dr. Pall indicated that we had failed to adequately reference his previous work. We do acknowledge his work on NO in CFS and related disorders. This is evidenced by the fact that we did reference to his work in each of the manuscripts criticized by Dr. Pall [1,3,4]. At the time we wrote the manuscripts, numerous studies providing scientific evidence supporting a role for NO and oxidative stress in CFS patients had already been published (e.g. [5–7]). Thus, we felt we were no longer obliged to reference to manuscripts hypothesising about the potential role of oxidative stress in CFS. Experimental data are superior to hypotheses. In addition, Dr. Pall challenged the originality of our proposed mechanism for explaining chronic pain in CFS (outlined in [1]). Dr. Pall claimed to have presented the hypothesis in two of his earlier manuscripts, published in 2000 [8] and 2002 [9]. However, the primary intentions of our hypothesis was to
link the observations by Vikman and colleagues (a study published in 2003 [10]) to the current understanding of CFS pathophysiology (Protein Kinase R (PKR) activation, the presence of chronic infections, etc.) and psychopathology (somatization, catastrophizing, activity-avoidance). Thus, it seems unlikely that Dr. Pall had already presented the same hypothesis even before the observations by Vikman et al. [10] were published. Second, it appears that Dr. Pall has misunderstood our proposed theory on intracellular immune deregulation and NO in CFS. He repeatedly stated that we had suggested that ‘‘elevated 37 kDa RNase L activity may generate excessive NO’’ [2]. On the contrary, we had repeatedly suggested that a mechanism distinct from cleaving of the 83 kDa RNase L enzyme may account for the observed increase in NO in CFS patients [1,3,4]. Neither the native RNase L enzyme, nor the cleaving fragments of the native enzyme, are capable of generating increased levels of NO. However, activation of the PKR enzyme leads to phosphorylation of the inhibitor of NF(nuclear factor)-jB (IjB) and consequent NF-jB activation, which in turn causes inducible nitric oxide synthetase (iNOS) expression [11]. iNOS generates increased production of NO by monocytes/macrophages. Fig. 1 on page 252 of [3] provides the reader with a schematically presentation of the distinction between the activation of the PKR enzyme and consequent increased NO availability, and the deregulation of the 20 ,50 -oligoadenylate (2-5A) synthetase/RNase L pathway in CFS. Finally, we would like to make a plead for better cooperation among CFS researchers around the world, rather than acting like competitors. In the past decade, CFS researchers around the world