Introduction Click here for more articles from the symposium
doi: 10.1111/joim.12241
Taming the cancer cell H. Jernberg Wiklund & B. Westermark From the Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Keywords: Cancer, cancer stem cells, cure, epigenetics, metabolism, treatment.
Even in countries with developed healthcare technology and systems, two of five patients with a cancer diagnosis die from their disease. Will we ever be able to ‘defeat’ cancer? In recent decades, our knowledge of cancer mechanisms has increased dramatically. There are striking examples of how our understanding of the molecular aberrations has led to novel therapeutic strategies, such as imatinib treatment of chronic myeloid leukaemia. This and other examples notwithstanding, what cures most malignancies is ‘brute force’, in other words surgical removal of the lump and irradiation. Needless to say, there is a need for more sophisticated modalities in cancer treatment based on the unique characteristics of the cancer cell and the cancer tissue that make them distinct from their nonneoplastic counterparts [1]. What is needed is not only ways to curb cancer growth and transform an acute disease into a chronic condition, but also to eradicate the cancer to the very last cell. Until only a few years ago, cancer was mainly regarded as a genetic disease in the sense that the aberrant behaviour of the cancer cell is driven by a limited set of accumulated mutations in critical regulatory genes, including oncogenes, tumour suppressor and DNA repair genes and others involved in the maintenance of genomic integrity. Focus was on structural changes in DNA (e.g. point mutations, deletions, amplifications and insertions) leading to a Darwinian evolution of the ‘fittest’ clonal population. This simplistic view has been challenged by seminal findings bringing metabolism and epigenetics into the spotlight; a considerably more complicated scenario is emerging, which may explain why it is so difficult ‘to win the war against cancer’. The aim of the 10th Key Symposium Taming the Cancer Cell was to bring together leading scientists, whose ideas may be of fundamental importance in creating the cancer treatment of tomorrow. Six of the speakers at the conference have contributed to the current issue of Journal of Internal Medicine.
2
ª 2014 The Association for the Publication of the Journal of Internal Medicine
Andy Feinberg is well known for his paintings of the epigenomic landscape in cancer. As described in his contribution [2], there are a number of examples suggesting that epigenetic modifications allow for rapid cellular selection in a changing environment, thus leading to a growth advantage for the tumour cells. Importantly, as Andy Feinberg indicates, this view does not in fact contradict the notion that cancer is a genetic disease, but rather it puts epigenetics at the centre of cancer biology, with the plasticity of the genome now being the platform for and not the consequence of transformation. A novel finding, presented in Feinberg’s article, is that the sites that show the greatest epigenetic variability in cancer are in fact those sites that also need to show stochastic variation during normal tissue development. The genes within these large blocks of hypermethylation thus include the most hypervariably expressed genes in human cancer. This may be of importance for developing cancer therapy focusing on targets of epigenetic dysregulation. The idea that epigenetic changes in susceptible cells precede rather than are a consequence of genetic changes in the cells of origin in cancer may prove to be useful for the identification of individuals at high risk of tumour development and thereby allow for stratification for active followup, e.g. by mammography. Cancer-prone processes such as iterative or chronic inflammation and/or tissue repair can be prevented by several mechanisms including vaccination against microorganisms, changes in lifestyle and administration of anti-inflammatory drugs. The impact of the microenvironment and metabolism on cell fate is elegantly highlighted by Sean Morrison [3], showing that the epigenome of stem cells is profiled by specific metabolites and thus influenced by the nutritional status of the cell. The notion that chromatin-modifying enzymes require metabolite co-factors for proper function may also have an impact on tumorigenesis. A striking example,
H. Jernberg Wiklund & B. Westermark
linking a specific genetic alteration to epigenetic changes, is the IDH1 gene leading to an increased production of 2-hydroxyglutarate followed by aberrant DNA and histone methylation, and impaired differentiation of progenitor cells. The revival of an earlier idea that cancer growth is fuelled by a limited number of clonogenic, cancerinitiating cells has caused substantial interest when considered within the cancer stem cell hypothesis. The influence of metabolism on the epigenome, as proposed by Sean Morrison, may indeed be applicable to cancer stem cells, as well providing interesting approaches for therapeutic intervention. The choice of fuel utilization and the bona fide metabolic programme selectively activated have in fact recently provided ways to uncover some of the molecular heterogeneity of tumours within transcriptionally defined subsets of diffuse large B-cell lymphoma [4]. Similar to normal stem cells, cancer stem cells are thought to be resistant to irradiation and chemotherapy. Underpinning this notion, there is a strong correlation between a patient’s response to treatment and secondary colony formation which quantifies the very essence of stem cells, that is, self-renewal capacity. Angelo Vescovi [5] discusses the important question of whether the phenotypic plasticity within cells of a given cancer population is crucial for governing stem cell functions. Drug tolerance within a tumour population should therefore not only be the result of a small population of cells that are intrinsically resistant to a particular drug but it is also possible that a drug-tolerant phenotype can transiently emerge as a consequence of exposure of cells to environmental factors. Thus, to gain insight into the tumour-initiating population and targets for therapy, it is important to consider the function of these cells rather than searching for biomarkers. Data from Angelo Vescovi have convincingly demonstrated that glioblastoma stem cells can indeed be manipulated to lose their capacity for self-renewal. It may be that the genetic aberrations of the glioblastoma cells cause the disease in the sense that they lead to the expansion and persistence of the gliomainitiating cancer stem cells. What Angelo Vescovi has shown is that the cells, despite their genetic aberrations, can change their phenotype, lose their self-renewal ability and differentiate in response to the addition of the differentiation factor BMP4. These findings are very promising,
Introduction: Taming the cancer cell
and, as Vescovi predicts, it is likely that BMP4 will enter the therapeutic arena. Pathologists may have contemplated the heterogeneous nature of malignant tumours with for instance regional differences in differentiation and grade and have undoubtedly considered the possible role of tumour stroma and invading inflammatory cells; however, it is mainly as a result of recent findings that the influence of the non-neoplastic component has been fully appreciated. Another complicating factor is the heterogeneity of the neoplastic population in cancer. Whilst Andy Feinberg has focused on the epigenetic background of heterogeneity, others have studied the genetic diversity and been able to identify private or unique alterations as well as genetic changes common to the entire tumour cell population. All these aspects of tumour heterogeneity are covered by Joan Seoane [6] and put into the perspective of precision medicine or targeted therapy, taking into account intratumoural heterogeneity. Current biomarkers in clinical use are blunt tools to aid therapy choice or longitudinal monitoring of treatment outcome. To eradicate the tumour, only targeted therapy against the origin of the cancer, that is, the common events, is expected to be effective. Seoane and De Mattos-Arruda [6] provide a list of clinical trials addressing issues relevant to precision medicine and recommend monitoring of circulating tumour cells and their DNA as an ‘online’ marker of the total number of tumourinitiating cells. The current, somewhat pessimistic, view is that all driver aberrations in a tumour cell need to be targeted for a successful outcome. This view has been challenged for example by Gerard Evan [7] and Dean Felsher [8]. These authors point out the possibility that there may be obligatory tumourassociated events common to all cancer cells, with the MYC pathway providing a typical example. MYC emerges as a master regulator of cancer initiation and growth, most probably dictated by both epigenetic and genetic contexts, but exerting its function as a general regulator of protein biogenesis. Thus, this universal regulator should be an ideal target for effective treatment in human cancer. As Dean Felsher clearly states, MYC inactivation does not inevitably lead to death of the tumour cells, but rather acts to cause a global shift in protein synthesis. MYC inactivation and tumour regression may thus restore the biology ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2014, 276; 2–4
3
H. Jernberg Wiklund & B. Westermark
of the cancer cell to a phenotype and function that appear to be closer to those of a normal cell. Whereas the ‘fight’ against cancer mostly remains a ‘battle against a superior enemy’, where the number of ideas far exceeds the number of working strategies, there are brilliant examples of success. One of the most prominent examples is that of the treatment of acute promyleocytic leukaemia (APL), which has been addressed by Hugues de Th e [9]. The combination of two chemical substances, retinoic acid and arsenic trioxide, leads not only to growth arrest and differentiation of tumour cells, but also to the complete loss of their self-renewal ability – and cure of the patient. Rice and de Th e [9] have studied the molecular mechanisms of the combination treatment and have been able to produce a mechanistic model to suggest that the APL paradigm can be extended to other tumour types. This idea in combination with the findings of other extremely interesting studies presented at the symposium leaves us with optimism for the future development of the field. The cancer cell can be ‘tamed’. Conflict of interest statement No conflict of interest to declare.
4
ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2014, 276; 2–4
Introduction: Taming the cancer cell
References 1 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–74. 2 Feinberg AP. Epigenetic stochasticity, nuclear structure, and cancer, and the implications for medicine. J Intern Med 2014; 276: 5–11. 3 Burgess RJ, Agathocleous M, Morrison SJ. Metabolic regulation of stem cell function. J Intern Med 2014; 276: 12–24. 4 Caro P, Kishan AU, Norberg E et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 2012; 22: 547–60. 5 Binda E, Reynolds BA, Vescovi AL. Stem cells from human glioblastomas: turpis Omen in Nomen? (An Evil Omen In The Name?) J Intern Med 2014; 276: 25–40. 6 Seoane J, De Mattos-Arruda L. The challenge of intratumour heterogeneity in precision medicine. J Intern Med 2014; 276: 41–51. 7 Soucek L, Whitfield J, Martins CP et al. Modelling Myc inhibition as a cancer therapy. Nature 2008; 455: 679–83. 8 Li Y, Casey SC, Felsher DW. MYC Inactivation Reverses Cancer. J Intern Med 2014; 276: 52–60. 9 Rice KL, de Th e H. The APL success story: curing leukemia through targeted therapies. J Intern Med 2014; 276: 61–70. Correspondence: Helena Jernberg Wiklund, PhD, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-751 85, Sweden. (fax: +46 18 558931; e-mail: [email protected]).
doi: 10.1111/joim.12241
Taming the cancer cell H. Jernberg Wiklund & B. Westermark From the Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Keywords: Cancer, cancer stem cells, cure, epigenetics, metabolism, treatment.
Even in countries with developed healthcare technology and systems, two of five patients with a cancer diagnosis die from their disease. Will we ever be able to ‘defeat’ cancer? In recent decades, our knowledge of cancer mechanisms has increased dramatically. There are striking examples of how our understanding of the molecular aberrations has led to novel therapeutic strategies, such as imatinib treatment of chronic myeloid leukaemia. This and other examples notwithstanding, what cures most malignancies is ‘brute force’, in other words surgical removal of the lump and irradiation. Needless to say, there is a need for more sophisticated modalities in cancer treatment based on the unique characteristics of the cancer cell and the cancer tissue that make them distinct from their nonneoplastic counterparts [1]. What is needed is not only ways to curb cancer growth and transform an acute disease into a chronic condition, but also to eradicate the cancer to the very last cell. Until only a few years ago, cancer was mainly regarded as a genetic disease in the sense that the aberrant behaviour of the cancer cell is driven by a limited set of accumulated mutations in critical regulatory genes, including oncogenes, tumour suppressor and DNA repair genes and others involved in the maintenance of genomic integrity. Focus was on structural changes in DNA (e.g. point mutations, deletions, amplifications and insertions) leading to a Darwinian evolution of the ‘fittest’ clonal population. This simplistic view has been challenged by seminal findings bringing metabolism and epigenetics into the spotlight; a considerably more complicated scenario is emerging, which may explain why it is so difficult ‘to win the war against cancer’. The aim of the 10th Key Symposium Taming the Cancer Cell was to bring together leading scientists, whose ideas may be of fundamental importance in creating the cancer treatment of tomorrow. Six of the speakers at the conference have contributed to the current issue of Journal of Internal Medicine.
2
ª 2014 The Association for the Publication of the Journal of Internal Medicine
Andy Feinberg is well known for his paintings of the epigenomic landscape in cancer. As described in his contribution [2], there are a number of examples suggesting that epigenetic modifications allow for rapid cellular selection in a changing environment, thus leading to a growth advantage for the tumour cells. Importantly, as Andy Feinberg indicates, this view does not in fact contradict the notion that cancer is a genetic disease, but rather it puts epigenetics at the centre of cancer biology, with the plasticity of the genome now being the platform for and not the consequence of transformation. A novel finding, presented in Feinberg’s article, is that the sites that show the greatest epigenetic variability in cancer are in fact those sites that also need to show stochastic variation during normal tissue development. The genes within these large blocks of hypermethylation thus include the most hypervariably expressed genes in human cancer. This may be of importance for developing cancer therapy focusing on targets of epigenetic dysregulation. The idea that epigenetic changes in susceptible cells precede rather than are a consequence of genetic changes in the cells of origin in cancer may prove to be useful for the identification of individuals at high risk of tumour development and thereby allow for stratification for active followup, e.g. by mammography. Cancer-prone processes such as iterative or chronic inflammation and/or tissue repair can be prevented by several mechanisms including vaccination against microorganisms, changes in lifestyle and administration of anti-inflammatory drugs. The impact of the microenvironment and metabolism on cell fate is elegantly highlighted by Sean Morrison [3], showing that the epigenome of stem cells is profiled by specific metabolites and thus influenced by the nutritional status of the cell. The notion that chromatin-modifying enzymes require metabolite co-factors for proper function may also have an impact on tumorigenesis. A striking example,
H. Jernberg Wiklund & B. Westermark
linking a specific genetic alteration to epigenetic changes, is the IDH1 gene leading to an increased production of 2-hydroxyglutarate followed by aberrant DNA and histone methylation, and impaired differentiation of progenitor cells. The revival of an earlier idea that cancer growth is fuelled by a limited number of clonogenic, cancerinitiating cells has caused substantial interest when considered within the cancer stem cell hypothesis. The influence of metabolism on the epigenome, as proposed by Sean Morrison, may indeed be applicable to cancer stem cells, as well providing interesting approaches for therapeutic intervention. The choice of fuel utilization and the bona fide metabolic programme selectively activated have in fact recently provided ways to uncover some of the molecular heterogeneity of tumours within transcriptionally defined subsets of diffuse large B-cell lymphoma [4]. Similar to normal stem cells, cancer stem cells are thought to be resistant to irradiation and chemotherapy. Underpinning this notion, there is a strong correlation between a patient’s response to treatment and secondary colony formation which quantifies the very essence of stem cells, that is, self-renewal capacity. Angelo Vescovi [5] discusses the important question of whether the phenotypic plasticity within cells of a given cancer population is crucial for governing stem cell functions. Drug tolerance within a tumour population should therefore not only be the result of a small population of cells that are intrinsically resistant to a particular drug but it is also possible that a drug-tolerant phenotype can transiently emerge as a consequence of exposure of cells to environmental factors. Thus, to gain insight into the tumour-initiating population and targets for therapy, it is important to consider the function of these cells rather than searching for biomarkers. Data from Angelo Vescovi have convincingly demonstrated that glioblastoma stem cells can indeed be manipulated to lose their capacity for self-renewal. It may be that the genetic aberrations of the glioblastoma cells cause the disease in the sense that they lead to the expansion and persistence of the gliomainitiating cancer stem cells. What Angelo Vescovi has shown is that the cells, despite their genetic aberrations, can change their phenotype, lose their self-renewal ability and differentiate in response to the addition of the differentiation factor BMP4. These findings are very promising,
Introduction: Taming the cancer cell
and, as Vescovi predicts, it is likely that BMP4 will enter the therapeutic arena. Pathologists may have contemplated the heterogeneous nature of malignant tumours with for instance regional differences in differentiation and grade and have undoubtedly considered the possible role of tumour stroma and invading inflammatory cells; however, it is mainly as a result of recent findings that the influence of the non-neoplastic component has been fully appreciated. Another complicating factor is the heterogeneity of the neoplastic population in cancer. Whilst Andy Feinberg has focused on the epigenetic background of heterogeneity, others have studied the genetic diversity and been able to identify private or unique alterations as well as genetic changes common to the entire tumour cell population. All these aspects of tumour heterogeneity are covered by Joan Seoane [6] and put into the perspective of precision medicine or targeted therapy, taking into account intratumoural heterogeneity. Current biomarkers in clinical use are blunt tools to aid therapy choice or longitudinal monitoring of treatment outcome. To eradicate the tumour, only targeted therapy against the origin of the cancer, that is, the common events, is expected to be effective. Seoane and De Mattos-Arruda [6] provide a list of clinical trials addressing issues relevant to precision medicine and recommend monitoring of circulating tumour cells and their DNA as an ‘online’ marker of the total number of tumourinitiating cells. The current, somewhat pessimistic, view is that all driver aberrations in a tumour cell need to be targeted for a successful outcome. This view has been challenged for example by Gerard Evan [7] and Dean Felsher [8]. These authors point out the possibility that there may be obligatory tumourassociated events common to all cancer cells, with the MYC pathway providing a typical example. MYC emerges as a master regulator of cancer initiation and growth, most probably dictated by both epigenetic and genetic contexts, but exerting its function as a general regulator of protein biogenesis. Thus, this universal regulator should be an ideal target for effective treatment in human cancer. As Dean Felsher clearly states, MYC inactivation does not inevitably lead to death of the tumour cells, but rather acts to cause a global shift in protein synthesis. MYC inactivation and tumour regression may thus restore the biology ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2014, 276; 2–4
3
H. Jernberg Wiklund & B. Westermark
of the cancer cell to a phenotype and function that appear to be closer to those of a normal cell. Whereas the ‘fight’ against cancer mostly remains a ‘battle against a superior enemy’, where the number of ideas far exceeds the number of working strategies, there are brilliant examples of success. One of the most prominent examples is that of the treatment of acute promyleocytic leukaemia (APL), which has been addressed by Hugues de Th e [9]. The combination of two chemical substances, retinoic acid and arsenic trioxide, leads not only to growth arrest and differentiation of tumour cells, but also to the complete loss of their self-renewal ability – and cure of the patient. Rice and de Th e [9] have studied the molecular mechanisms of the combination treatment and have been able to produce a mechanistic model to suggest that the APL paradigm can be extended to other tumour types. This idea in combination with the findings of other extremely interesting studies presented at the symposium leaves us with optimism for the future development of the field. The cancer cell can be ‘tamed’. Conflict of interest statement No conflict of interest to declare.
4
ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2014, 276; 2–4
Introduction: Taming the cancer cell
References 1 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–74. 2 Feinberg AP. Epigenetic stochasticity, nuclear structure, and cancer, and the implications for medicine. J Intern Med 2014; 276: 5–11. 3 Burgess RJ, Agathocleous M, Morrison SJ. Metabolic regulation of stem cell function. J Intern Med 2014; 276: 12–24. 4 Caro P, Kishan AU, Norberg E et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 2012; 22: 547–60. 5 Binda E, Reynolds BA, Vescovi AL. Stem cells from human glioblastomas: turpis Omen in Nomen? (An Evil Omen In The Name?) J Intern Med 2014; 276: 25–40. 6 Seoane J, De Mattos-Arruda L. The challenge of intratumour heterogeneity in precision medicine. J Intern Med 2014; 276: 41–51. 7 Soucek L, Whitfield J, Martins CP et al. Modelling Myc inhibition as a cancer therapy. Nature 2008; 455: 679–83. 8 Li Y, Casey SC, Felsher DW. MYC Inactivation Reverses Cancer. J Intern Med 2014; 276: 52–60. 9 Rice KL, de Th e H. The APL success story: curing leukemia through targeted therapies. J Intern Med 2014; 276: 61–70. Correspondence: Helena Jernberg Wiklund, PhD, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-751 85, Sweden. (fax: +46 18 558931; e-mail: [email protected]).
