Cancer surveys最新文献

The evolution of the malignant phenotype requires a set of genetic and epigenetic changes in sets of genes responsible for regulation of normal growth and cell death, of "social behaviour" and differentiation. The sum of these changes, not only the sequence, determines the malignancy as well as its grade. The probability of invasiveness shows a remarkable relationship to morphological changes, which in turn prove to be accompanied by a multitude of discrete molecular perturbations. Some of these can be characterized as functional, others as inductive with respect to their participation in the process. Since only the functional changes regulate malignant behaviour per se, it is an important task for future research to assemble a set of such changes, find markers for them and combine morphological and molecular indicators to achieve prognostically optimal scores. It should be emphasized, though, that rational use of such scores using biopsy samples as a source of information cannot be defined until biopsy strategies have been standardized and optimized.

In the last decade there has been major progress in understanding the multiple steps involved in cancer cells developing their malignant potential. Study of bladder cancer has provided important information during this period and helped to identify HLA class I and wild type normal TP53 as potential probes for gene therapy studies. Given the magnitude of genetic damage that is associated with the clonal development of bladder cancer, and particularly the number of cellular mechanisms that have been highjacked in the development of terminal metastatic disease, it is obviously highly unlikely that a single gene therapy involving HLA class I alone would work in terminal metastatic disease. However, it seems possible that HLA-B7 treatment of patients with bladder cancer who are candidates for salvage cystectomy would benefit such patients. If it were to work, it could provide a whole new approach to managing superficial tumours. However for patients with extensive metastatic disease, progress could come from investing more effort in uncoverinlg the genetic basis of the chemosensitivity of germ cell tumours and understanding the basis of the normal checkpoints of meiosis and the role of TP53. This could provide a completely new approach to gene therapy that might be exploited even in patients with advanced metastatic disease. Such a tetraploidal construct combined with allogeneic HLA class I and incorporated into a low pathogenic lytic viral construct to induce oncolysis with some form of tissue promoter to focus the cell types in which the genes will be activated could provide ideal effective gene therapy.

Squamous cell carcinoma of the skin and melanoma are the rare progeny of precancerous lesions that usually remain stable or regress. For SCC the sequence appears to include TP53 mutant clones in normal skin; dysplasia; carcinoma in situ; and SCC. When such lesions are contiguous, their TP53 mutations are consistent with a single clonal lineage. The set of TP53 mutations in tumours is more restricted than in precancers, suggesting additional selection. Melanoma lies at the end of a continuum including mole, dysplastic naevus, radial growth melanoma and vertical growth. The genetics of melanoma is less clear. Basal cell carcinomas seem to arise without a precancer and contain mutations in TP53 and PTCH. Childhood sunlight exposure directs the location and frequency of precancers. For melanoma, its effects on intermittently exposed body sites are superimposed on the effect at sites chronically exposed. SCC precancers and tumours, BCC tumours and melanoma cell lines contain UV induced mutations. Sun exposed skin of normal individuals contains thousands of small clones of TP53 mutated cells. Predisposition to sunlight induced precancer is a multigenic trait involving factors such as hair and skin color, DNA repair proficiency and mole type and number. These each contribute a relative risk on the order of two to four. Familial predisposition to dysplastic naevi carries a larger risk. The cell of origin for melanoma is uncontroversial, and the proposed hair follicle origin of BCC is consistent with the presence of stem cells in the bulge region. The origin of SCCs and the arrangement of interfollicular stem cell compartments are less clear. Clonal expansion of the initial mutated cell may also be driven by sunlight. When a mutation confers apoptosis resistance, as TP53 mutations do, subsequent UV exposure will be more likely to kill normal cells than mutants. The latter can expand into a clone, only one cell of which need be mutated again. Immunosuppressant drugs may have the same effect as UV, facilitating the clonal expansion of precancers. In the absence of exogenous influences, mutant clones and precancers tend to regress. There is little evidence that regression of precancers is immunological, though regression of melanoma appears to be. The chemotherapeutic agent 5-FU causes regression of dysplasias by removing initiated cells, perhaps by enhancing apoptosis. In contrast, retinoic acid temporarily suppresses clonal expansion. Most sunscreens are mutagenic, with as yet unknown consequences. Mice develop dysplasias and SCCs after UV irradiation. Initiation and clonal expansion of dysplasias is UV driven, but conversion to SCC and subsequent growth involve spontaneous events. With chemical carcinogens mice develop papillomas that usually regress and thus are precancers. Tumour promotion yields abundant low risk papillomas that contain Hras1 mutations but rarely progress to SCC. High risk papillomas are infrequent but do convert to SCC, particul

The advantage of BCG immunotherapy over intravesical chemotherapy in superficial bladder cancer has been most apparent in patients with carcinoma in situ (CIS), where complete response is increased from 50% to more than 70% and the proportion of patients remaining disease free for 5 years is increased from 20% to 40%. Similar advantages have been reported using suboptimal BCG treatment schedules in patients with recurrent stage Ta, T1 tumours. BCG provides long term protection from tumour recurrence and, unlike chemotherapy, reduces tumour progression. The observed relative increased sensitivity of CIS to BCG and the occasional failure of BCG to demonstrate significant superiority over mitomycin C in the prevention of tumour appear to be related to the use of suboptimal BCG treatment schedules. With maintenance BCG using 3 weekly instillations at 6 month intervals, patients with papillary tumours fare even better than patients with CIS, and tumour progressio is even further reduceld. Chemotherapy is appropriate for patients who are at very low risk of tumour progression and those who fail to respond to BCG, but overall the results of BCG immunotherapy are superior for patients with either CIS or Ta, T1 transitional cell carcinoma.

The molecular genetic changes reported in bladder tumours can be classified as primary and secondary aberrations. Primary molecular alterations may be defined as those directly related to the genesis of cancer. These are frequently found as the sole abnormality and often associated with particular tumours. We describe primary abnormalities as having a dual nature: those events involved in the production of low grade/well differentiated neoplasms, which would destabilise cellular proliferation but have minimal or no effects on cellular "social" interactions or differentiation or on rate of cell death or apoptosis; and others leading to high grade/poorly differentiated tumours, which would disrupt growth control, including cell cycle and apoptosis regulation and have a major impact on cellular differentiation. There is evidence that a target site(s) for a primary event(s) in low grade papillary superficial bladder tumours may reside on chromosome 9. However, a candidate for the initiation of high grade, flat carcinoma in situ lesions has not been yet elucidated. Novel approaches utilizing tissue microdissection techniques and molecular genetic assays are needed to shed light on this subject. Secondary genetic or epigenetic abnormalities may be fortuitous or may determine the biological behaviour of the tumour. Multiple molecular abnormalities are identified in most human cancers studied, including bladder neoplasms. The accumulation, rather than the order, of these genetic alterations is the critical factor that grants synergetic activity. In this regard, it is noteworthy that most of the altered genes act upon the two recognized critical growth and senescence pathways, TP53 and RB. There is a major requirement for well designed, randomized, prospective trials evaluating the strongest candidate markers in order to validate many reported exploratory studies. Although great enthusiasm exists with the application of various tumour makers in the management of bladder cancer, concrete clinical recommendations must be tempered at this time. As with preneoplastic conditions, the discrepancies that exist between clinical investigators regarding the significance of identifying such morphological changes have imposed crucial limitations. Another drawback has been the confusing nomenclature utilized and the lack of reproducibility in interpretation of morphological criteria. Molecular analyses utilizing well characterized preneoplastic lesions, including dysplasia samples, need to be pursued. This in turn may provide the needed information to realise the clinical relevance of detecting genetic instability, as well as molecular or epigenetic alterations, in otherwise morphologically normal appearing urothelium and preneoplastic lesions. The need now is to translate the newly developed scientific information into diagnostic and prognostic strategies, which in turn will prolong patient survival and quality of life.

Oesophageal cancer is the fifth most frequent cause of cancer death world wide and most of these cancers occur in developing countries. The survival rate for SCC or ADCs of the oesophagus is equally poor, mainly due to their late detection and the poor efficacy of the therapy. A short review of the natural history of these cancers, and in particular the occurrence of genetic and cellular alterations associated with cancer progression, is presented and discussed in the context of the relevance to aetiology and pathogenesis. SCCs and ADCs show a distinct pattern of TP53 mutations, namely a high prevalence of G > A transitions at CpG sites in ADCs whereas in SCCs a higher prevalence of G to T transversions and mutations at A:T base pairs is present. In both types of cancers TP53 mutations occur very early and are followed by the accumulation of other genetic alterations during the process of oesophageal carcinogenesis. The value of these genetic alterations in assessing the multifocal monoclonal origin of oesophageal cancer is also addressed.

Bladder cancer has classically been associated with exogenous risk factors, and a large literature has identified risk factors associated with the genesis of transitional cell carcinoma. Only recently have efforts been made to identify host factors and to evaluate possible changes in tumour presentation and biology, including grade and stage, in association with these risk factors. The available literature appears to demonstrate alterations in tumour biology associated with environmental carcinogens. Various studies have suggested a consistent upgrading of bladder cancer stage and grade as a result of cigarette smoking and high risk occupational exposures. It is important, however, that all factors associated with increased risk for bladder cancer be more extensively evaluated in assessing the validity of this concept.

Invasive bladder cancer is associated with locoregional and distant metastases. To improve the outcome of management, systemic chemotherapy has been combined with locoregional treatment. Programmes have been structured in which chemotherapy is administered before or after definitive radiotherapy or surgery, or in combination with radiotherapy. Most randomized trials to date have failed to define a survival benefit from initial chemotherapy, but evidence is emerging that classical adjuvant chemotherapy may improve survival. New cytotoxic agents, including paclitaxel and gemcitabine, accompanied by an emerging understanding of the factors governing cytotoxic drug resistance, may also lead to better management.