Programmed Cell Death in Tumours and Tissues

cal treatment of retroperitoneal lymph nodes in patients with testicular cancer is made quite firmly including a comment relating to combination chemotherapy that 'azoospermia appears to persist for years if not permanently.' Elsewhere in the volume however it is noted that 'Retrospective review of a group of 28 patients indicated normal sperm counts in 46% of patients after chemotherapy.' These differences of view serve only to emphasise the problems which currently still face the profession as does the statement in relation to exenteration that, 'at the start of the operative procedure the para-aortic nodes are palpated and any enlarged nodes submitted for frozen section histology.' It is noted that 'metastatic disease in the para-aortic nodes is an absolute contraindication to pelvic exenteration.' Nonetheless, 'formal para-aortic lymphadenectomy is advised in the absence of suspicious lymph nodes.' If the whole operation is pointless in the presence of metastases it hardly seems necessary to do the resection if metastases are absent. Perhaps this will be clarified in a further edition. There is a similar inconsistency in considering the follow up of transitional cell tumours of the bladder where it is noted that 'Among the 600 patients with transitional cell carcinoma of the bladder, 4% developed upper tract lesions after a delay of approximately 61 months.' The subsequent advice is to have an annual radiological examination of the upper tract for 2 years after initial diagnosis and treatment of either an upper tract or bladder transitional cell carcinoma. This seems inconsistent if most of the upper tract occurrences in those treated for bladder carcinoma will occur subsequent to 2 years. It is always possible to find inconsistencies in any work of reference and I have mentioned those which I have found, merely to draw attention to the fact that I have read every page of this book with interest and enjoyment. Each chapter is well written and beautifully illustrated, whilst the sections towards the end of the book dealing with the current knowledge concerning the possibilities for chemotherapy in each group of tumours, the possible role of radiation therapy, imaging techniques, tips on intestinal and vascular surgery and observations upon medical evaluation, nutritional and metabolic care, psychosexual support and care for the terminally ill patient are thoughtful and most relevant additions to a surgical text. In my view, every department of urology should have two copies of this book, one in its departmental library and the other immediately available in the operating suite so that it may be consulted at any time before or during an operation for cancer of the urinary tract.

cal treatment of retroperitoneal lymph nodes in patients with testicular cancer is made quite firmly including a comment relating to combination chemotherapy that 'azoospermia appears to persist for years if not permanently.' Elsewhere in the volume however it is noted that 'Retrospective review of a group of 28 patients indicated normal sperm counts in 46% of patients after chemotherapy.' These differences of view serve only to emphasise the problems which currently still face the profession as does the statement in relation to exenteration that, 'at the start of the operative procedure the para-aortic nodes are palpated and any enlarged nodes submitted for frozen section histology.' It is noted that 'metastatic disease in the para-aortic nodes is an absolute contraindication to pelvic exenteration.' Nonetheless, 'formal para-aortic lymphadenectomy is advised in the absence of suspicious lymph nodes.' If the whole operation is pointless in the presence of metastases it hardly seems necessary to do the resection if metastases are absent. Perhaps this will be clarified in a further edition.
There is a similar inconsistency in considering the follow up of transitional cell tumours of the bladder where it is noted that 'Among the 600 patients with transitional cell carcinoma of the bladder, 4% developed upper tract lesions after a delay of approximately 61 months.' The subsequent advice is to have an annual radiological examination of the upper tract for 2 years after initial diagnosis and treatment of either an upper tract or bladder transitional cell carcinoma. This seems inconsistent if most of the upper tract occurrences in those treated for bladder carcinoma will occur subsequent to 2 years.
It is always possible to find inconsistencies in any work of reference and I have mentioned those which I have found, merely to draw attention to the fact that I have read every page of this book with interest and enjoyment. Each chapter is well written and beautifully illustrated, whilst the sections towards the end of the book dealing with the current knowledge concerning the possibilities for chemotherapy in each group of tumours, the possible role of radiation therapy, imaging techniques, tips on intestinal and vascular surgery and observations upon medical evaluation, nutritional and metabolic care, psychosexual support and care for the terminally ill patient are thoughtful and most relevant additions to a surgical text.
In my view, every department of urology should have two copies of this book, one in its departmental library and the other immediately available in the operating suite so that it may be consulted at any time before or during an operation for cancer of the urinary tract. Our understanding of the relationship between immune status and malignancy has a long and somewhat controversial history. At one extreme of this controversy, immunological deficits are held to be intimately connected with progression of malignant disease; others have dismissed any immunological defects that may be found as post hoc phenomena, a consequence of malignant disease rather than a necessary precursor of it. The field is also complicated by the range of (not easily reproducible) in vitro techniques that have been used to define immunological defects and to probe their mechanistic basis. To this one can add the basic dilemma posed by insufficient knowledge of the in vivo role both of the effector cell types being studied and their putative regulatory mechanisms. For example, the regulation of natural killer (NK) cell activity by monocytes begs the questions of whether NK cell activity is relevant to the development of malignancy, and if it is, whether NK activity is regulated by monocytes in vivo.
The authors are fully aware of these dilemmas, and they seek to avoid them by providing a very comprehensive assessment of the widest possible range of candidate regulatory and suppressive mechanisms that could influence the growth of malignant tumours. Whilst this detailed scholarship is an admirable summation of these possible mechanisms, in the process the major disadvantage of this book quickly becomes apparent. The problem is that the majority of the book appears to have been written in 1984-5, with a few later additions in early 1987. In many fields, this delay would not vitiate the endeavour, but immunology is develop-ing rapidly, and particularly within the last 3-4 years when several fundamental conceptual advances have occurred. The most notable is probably the Bjorkman model for the structure of MHC antigens, with consequences for the nature of T cell recognition and the mechanisms of antigen processing, transport and presentation. Another development that is now more widely recognised is that of antigen processing by B lymphocytes. The earlier explanation of cognate help which involved antigen forming a bridge between receptors of T and B cells is alluded to in the introduction to the chapter on suppressor cells and human malignancy. The current view is that the B cell receptor allows preferential uptake of native antigen which is processed, followed by presentation of associated T cell epitope(s) to CD4 T cells in the context of the B cell's class II MHC.
As well as producing rapid developments in some areas, immunologists also have a remarkable capacity to lose faith (or at least lose interest) in others. As briefly discussed at the end of the concluding chapter of the book, suppressor cells are very much in the latter category. The current lack of willingness on the part of some investigators to countenance a major in vivo role for suppressor cells, whether or not as a distinct functional population of cells, may subsequently prove to be an extreme view, but it contrasts very strongly with the zeitgeist so apparent in the earlier chapters of the book.
One is left with the feeling that whilst the detailed discussions of suppressor mechanisms developed in the book are valid within their own terms of reference, time has moved on too far and too fast for these considerations to have a major impact on current thinking in this area, and necessarily limits the value of the book even to a more general readership. The renaissance of interest in programmed cell death in tumours, after a relatively low key burst of excitement in the topic in the early 1970's, has been driven to a large degree by the application of molecular biological techniques to this fascinating topic. A review of the subject is therefore most welcome. The Bowens' book has been expertly timed: it precedes the publication of a Cold Spring Harbor publication on programmed cell death by a few months. When CSH publishes a monograph (after holding a meeting last Spring) it suggests that programmed cell death has come of age! How does a cell die? Bowen and Bowen give us plenty of descriptions in their book: death by cell deletion, by necrosis, apoptosis (programmed cell death), accidental cell death, induced cell death, death by differentiation and death by autolysis. Each of these definitions attempts to clarify the loss of cells by natural or unnatural means, by suicide or by murder. Undoubtedly, the task of trying to create order from this semantic jungle is an extremely difficult one for the authors, but the thermodynamic differences which delineate programmed cell death from necrosis surely lie at the centre of this tangled mass: programmed cell death is initially uphill and necrosis downhill. So, whilst the book serves as a basic introduction to this exciting area, it did not clarify for this reader whether some of these various descriptions of cell death are really just semantic delineations, or whether there are many ways that a cell can die, uphill or down. For example, in discussing apoptosis as defined by Wyllie and colleagues, it is stated that '(their) description of apoptosis ... is not applicable to all systems. Specialised cells in both plants and animals can differentiate to death along specific pathways' (page 31). But how do these differentiated cells die? Recent reports on the fate of human neutrophils suggest that their fate certainly is apoptosis. And this make sense: the uncontrolled breakdown of this differentiated cell so as to release its armory of lytic enzymes would be a disaster for the host. Perhaps the detailed accounts of the Bowens' own research (rather parochially described at times), on the role of degradative enzymes in programmed cell death, presented a counter-intuitive slant to the description of a controlled, uphill process driven by the early activation of new gene expression.
After a brief introduction to the concept of programmed cell death in the first chapter the authors move on to the mechanistic aspects. Some recent examples of the temporal sequence of events which initiate programmed cell death attempt counterbalance their bias towards the role of lytic hydrolases and phosphatases. However, it is a shame that the central role of calcium as a signal which might initiate gene transcription necessary for programmed cell death is not tackled in any depth, and the paradox of a calcium signal in thymocytes triggering the opposing processes of mitosis and apoptosis is not discussed, despite the elegant studies of Orrenius and colleagues who have tried to tackle this problem. The same type of paradox arises in the observations of Lockshin and coworkers that the activation of the transcriptional cascade c-fosc-mychsp 70 is conserved between mitosis and the castration-induced programmed cell death observed in the rat ventral prostate; their work is not referred to. I was eager to read how the authors, who have been in the vanguard of those studying cell death, might interpret current puzzles of these types. It is in these very fields of signalling and changes in gene expression that progress is likely to be made in our understanding of mechanisms initiating and controlling programmed cell death and this is where all the excitement is at present. The beautiful work of Horvitz and his colleagues on the identification of the genes ced-3 and ced-4, which are responsible for the patterns of programmed cell death in C.elegans, is not discussed, and no reference is made to the expression of TRPM-2 gene which is a programmed cell death-associated gene expressed in the prostate. This is a shame because it places the book amongst earlier monographs which have, necessarily, focussed on the histopathology of cell death rather than its mechanics, and this old-fashioned approach greatly diminishes the impact of the book and its timeliness.
The style of the text suggests that it is targeted to the final year undergraduate or first year postgraduate and much of the areas reviewed might be valuable to a novice in the field, despite caveats regarding style and specific content. The authors include an appendix of methodology, which reflects further their prejudices as to the importance of phosphatases in programmed cell death. It is surprising that they do not include a discussion of the problems of detecting the apoptotic cell nor any methodological hints on assaying an important biochemical marker of apoptosis, the induction of internucleosomal strand breaks in DNA. Inside the book there is definitely another book struggling to be born, the germ of which is very well written in comparison to much of the rest; this is on the mode of action of cytokines and it forms almost half of the text. If this was given less prominence and the emerging biochemical and molecular biological aspects of programmed cell death were reviewed in detail, a rigorously edited book would have more appeal.