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Cancer: Undifferentiation or specialization?
Oral Oncology (2005) 41, 655–656
http://intl.elsevierhealth.com/journals/oron/
SHORT COMMUNICATION
Cancer: Undifferentiation or specialization? Abel Garcı´a-Garcı´a a b
a,*
, Manuel Somoza-Martin b, Jose M. Gandara-Rey
b
Oral Surgery Unit, School of Dentistry, University of Santiago de Compostela, Spain Facultad de Medicina y Odontologı´a Entrerrios s/n, 15700 Santiago de compostela, Spain
Received 14 January 2005; accepted 5 February 2005
Solid malignant tumours are characterized clinically by the invasion and destruction of the organ in which they originate, and subsequent metastasis, i.e. invasion and destruction of other organs. Diagnosis is conventionally based on histological exam: pathologists are able to distinguish dozens of varieties of malignant neoplasm on the basis of visual appearance alone. It may sometimes appear that different malignant neoplasms are different diseases, in view of different histological appearance, different rates of development, and different responses to the treatment options currently available. However, they all behave in the same way: local invasion and destruction, followed by metastasis. Interestingly, conventional histological diagnosis is based among other things on the presence of isolated multinucleate cells or cells showing aberrant mitosis, within a matrix of undifferentiated cells. Are these isolated cells key causal contributors to the neoplasm’s capacity for invasion and metastasis? Or are they simply a consequence of the metabolic activity of the new tissue, associated with cellular necrosis? It seems to me difficult to believe that cells with this morphology are able to withstand repeated mitoses, or that they show strong metabolism favouring survival.
* Corresponding author. Tel.: +34606461881. E-mail address: [email protected] (A. Garcı´a-Garcı´a).
The presence of mutations in specific genes (such as p53) is apparently critical for the development of malignant neoplasms, and has led research to focus on such mutations as the ‘‘causes’’ of cancer. However, these mutations do not necessarily cause cancer: for example, patients with Li– Fraumeni syndrome typically have inherited p53 mutations, but nevertheless reach advanced age without developing neoplasms.1 In fact, it may be that these mutations do not cause cancer directly, but rather that they create an environment that favours the onset of the gene expression profiles leading to cancer. Massive parallel analyses of gene expression using DNA microarrays have shown that a large number of genes in neoplastic tissues show increased expression with respect to the corresponding normal tissue. At the same time, many genes expressed in the normal tissue are no longer expressed in the neoplastic tissue.2,3 Nevertheless, the morphological and behavioural differences between different tumours may be more closely related to the genetic heritage of the original undisturbed tissue than to the genes newly expressed during the neoplastic process. Pathologists use the term ‘‘undifferentiation’’ to refer to the cellular processes undergone by tumours, in view of the dramatic destructuring of tissue architecture. However, given the large number of genes expressed in malignant neoplasms, might we not also talk of ‘‘tumour differentiation’’? In
1368-8375/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2005.02.002
656
A. Garcı´a-Garcı´a et al.
1944, Schro ¨dinger4 drew attention to the existence of a mathematical relationship between the number of elements participating in a biological process (n) and the degree of precision with which that process can be expected to occur (p): p/
pffiffiffi n
In the present context, we can take n to be the number of genes expressed. The greater the number of genes expressed, the more the tumour will be governed by ‘‘its own rules’’, as opposed to the ‘‘rules’’ of the original tissue. The large number of genes expressed in neoplastic tumours suggests that the observed morphological undifferentiation is paralleled by a considerable increase in precision, i.e. differentiation in a different direction to that characterizing the normal tissue. This differentiation is what gives these cells their capacity to invade, destroy and metastasize. We are dealing here with a sophisticated program common to all metastatic cells, with high precision as indicated by Schro ¨dinger’s relation; and this sophistication and high precision suggests that the program is ‘‘designed’’ for some important and physiological biological function (perhaps during embryological development or indeed some biological process currently unknown). In other words, cancer can be seen as a pathological activation of an originally physiological program of cell behaviour. It seems though as if neoplastic cells are incapable of entirely ‘‘forgetting’’ their genetic heritage (i.e. the gene expression patterns characteristic of the original tissue); indeed, this is why pathologists are able to identify neoplasms originating from different tissues. It is also possible that this ‘‘genetic heritage’’ is responsible for the different behaviour of different tumours: in a sense, this heritage can
be seen as a burden from which the neoplastic cell is unable to free itself. In fact, I would go so far as to suggest that the complex gene expression profile of cancer may be initiated in the absence of any underlying mutation, simply in response to external factors. Most treatment approaches used at present aim at destruction of the neoplastic tissue, whether surgically or by radio- or chemotherapy. Perhaps though it is time to investigate possible physiological functions of the gene expression profile, and to attempt to determine how this physiological expression is controlled, with the aim of inducing the same or similar mechanisms of control to prevent cancer. It is my view that a more profound understanding of these issues may help in our drive to better understand cancer, and in our efforts to design more effective treatments. In any case, it seems clear that studies of gene expression using DNA microarrays offer us a more integrated vision of cancer than conventional morphological approaches, and at the same time favour exploration of complex processes that are unlikely to be revealed by visual appearance alone.
References 1. Hisada M, Garber JE, Fung CY, Fraumeni Jr JF, Li FP. Multiple primary cancers in families with Li–Fraumeni syndrome. J Natl Cancer Inst 1998;90:606–11. 2. Mendez E, Cheng C, Farwell DG, et al. Transcriptional expression profiles of oral squamous cell carcinoma. Cancer 2002;95:1482–94. 3. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530–6. 4. Schro ¨dinger E. What is life? The physical aspect of the living cell. Cambridge University Press; 1944.
http://intl.elsevierhealth.com/journals/oron/
SHORT COMMUNICATION
Cancer: Undifferentiation or specialization? Abel Garcı´a-Garcı´a a b
a,*
, Manuel Somoza-Martin b, Jose M. Gandara-Rey
b
Oral Surgery Unit, School of Dentistry, University of Santiago de Compostela, Spain Facultad de Medicina y Odontologı´a Entrerrios s/n, 15700 Santiago de compostela, Spain
Received 14 January 2005; accepted 5 February 2005
Solid malignant tumours are characterized clinically by the invasion and destruction of the organ in which they originate, and subsequent metastasis, i.e. invasion and destruction of other organs. Diagnosis is conventionally based on histological exam: pathologists are able to distinguish dozens of varieties of malignant neoplasm on the basis of visual appearance alone. It may sometimes appear that different malignant neoplasms are different diseases, in view of different histological appearance, different rates of development, and different responses to the treatment options currently available. However, they all behave in the same way: local invasion and destruction, followed by metastasis. Interestingly, conventional histological diagnosis is based among other things on the presence of isolated multinucleate cells or cells showing aberrant mitosis, within a matrix of undifferentiated cells. Are these isolated cells key causal contributors to the neoplasm’s capacity for invasion and metastasis? Or are they simply a consequence of the metabolic activity of the new tissue, associated with cellular necrosis? It seems to me difficult to believe that cells with this morphology are able to withstand repeated mitoses, or that they show strong metabolism favouring survival.
* Corresponding author. Tel.: +34606461881. E-mail address: [email protected] (A. Garcı´a-Garcı´a).
The presence of mutations in specific genes (such as p53) is apparently critical for the development of malignant neoplasms, and has led research to focus on such mutations as the ‘‘causes’’ of cancer. However, these mutations do not necessarily cause cancer: for example, patients with Li– Fraumeni syndrome typically have inherited p53 mutations, but nevertheless reach advanced age without developing neoplasms.1 In fact, it may be that these mutations do not cause cancer directly, but rather that they create an environment that favours the onset of the gene expression profiles leading to cancer. Massive parallel analyses of gene expression using DNA microarrays have shown that a large number of genes in neoplastic tissues show increased expression with respect to the corresponding normal tissue. At the same time, many genes expressed in the normal tissue are no longer expressed in the neoplastic tissue.2,3 Nevertheless, the morphological and behavioural differences between different tumours may be more closely related to the genetic heritage of the original undisturbed tissue than to the genes newly expressed during the neoplastic process. Pathologists use the term ‘‘undifferentiation’’ to refer to the cellular processes undergone by tumours, in view of the dramatic destructuring of tissue architecture. However, given the large number of genes expressed in malignant neoplasms, might we not also talk of ‘‘tumour differentiation’’? In
1368-8375/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2005.02.002
656
A. Garcı´a-Garcı´a et al.
1944, Schro ¨dinger4 drew attention to the existence of a mathematical relationship between the number of elements participating in a biological process (n) and the degree of precision with which that process can be expected to occur (p): p/
pffiffiffi n
In the present context, we can take n to be the number of genes expressed. The greater the number of genes expressed, the more the tumour will be governed by ‘‘its own rules’’, as opposed to the ‘‘rules’’ of the original tissue. The large number of genes expressed in neoplastic tumours suggests that the observed morphological undifferentiation is paralleled by a considerable increase in precision, i.e. differentiation in a different direction to that characterizing the normal tissue. This differentiation is what gives these cells their capacity to invade, destroy and metastasize. We are dealing here with a sophisticated program common to all metastatic cells, with high precision as indicated by Schro ¨dinger’s relation; and this sophistication and high precision suggests that the program is ‘‘designed’’ for some important and physiological biological function (perhaps during embryological development or indeed some biological process currently unknown). In other words, cancer can be seen as a pathological activation of an originally physiological program of cell behaviour. It seems though as if neoplastic cells are incapable of entirely ‘‘forgetting’’ their genetic heritage (i.e. the gene expression patterns characteristic of the original tissue); indeed, this is why pathologists are able to identify neoplasms originating from different tissues. It is also possible that this ‘‘genetic heritage’’ is responsible for the different behaviour of different tumours: in a sense, this heritage can
be seen as a burden from which the neoplastic cell is unable to free itself. In fact, I would go so far as to suggest that the complex gene expression profile of cancer may be initiated in the absence of any underlying mutation, simply in response to external factors. Most treatment approaches used at present aim at destruction of the neoplastic tissue, whether surgically or by radio- or chemotherapy. Perhaps though it is time to investigate possible physiological functions of the gene expression profile, and to attempt to determine how this physiological expression is controlled, with the aim of inducing the same or similar mechanisms of control to prevent cancer. It is my view that a more profound understanding of these issues may help in our drive to better understand cancer, and in our efforts to design more effective treatments. In any case, it seems clear that studies of gene expression using DNA microarrays offer us a more integrated vision of cancer than conventional morphological approaches, and at the same time favour exploration of complex processes that are unlikely to be revealed by visual appearance alone.
References 1. Hisada M, Garber JE, Fung CY, Fraumeni Jr JF, Li FP. Multiple primary cancers in families with Li–Fraumeni syndrome. J Natl Cancer Inst 1998;90:606–11. 2. Mendez E, Cheng C, Farwell DG, et al. Transcriptional expression profiles of oral squamous cell carcinoma. Cancer 2002;95:1482–94. 3. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530–6. 4. Schro ¨dinger E. What is life? The physical aspect of the living cell. Cambridge University Press; 1944.