Clinical Significance of Apoptosis

Physiological roles of Apoptosis

Apoptosis has a role in the growth and development of many tissues including neurons,the human retina and maturation of lymphocytes in the thymus.In the haematopoietic system, apoptosis helps to ensure that the masive rate of new cell production in the bone marrow is offset by a commensurate rate of cell death in the periphery.

Focal apoptosis plays an important role in many normal embryonic processes such as the development of the lumina of tubular structures,the fashioning of limbs and the formation of interdigital clefts.Apart from its role in normal oncogenesis , it is also important in teratogeny.A number of teratogenic agents have been found to cause massive apoptosis at their site of action.In some cases the abnormalities have been accounted for by the apoptosis observerd within a few hours of treatment. Endocrine-dependent atrophy and hyperplasia also involve apoptosis.

In immune reactions

In immune reactions some cytotoxic T-lymphocytes destroy their target cells by causing them to undergo apoptosis.

Apoptosis is also thought to play an important role in the inflammatory response.The acute inflammatory response is a beneficial process,that has developed as part of the host response,to control and limit tissue damage resulting from injury and infection.The cellular events of accute inflammation are heralded by the tissue inflags of a large number of neutrophil granulocytes.These cells have a well established potetial to injure tissues by a variety of mechanisms and have been implicated in a number of inflammantory diseases in several organs.It was once assumed that the neutrophils disintegrated in the tissues , but evidence now suggests that intact netrophils are engulphed by macrophages at the sites of inflammation. This involves morphological changes and a chromatin fragmantation pattern, characteristic of apoptosis,within the neutrophilis that triggers recognition by the macrophages.This mechanism of neutrophilis disposal is an injury-limiting mechanism that is important in the normal resolution of the inflammation.

Downregulation of the immune response may constitute a stage when lymphocytes undergo apoptosis.This is demonstrated by the fact that,once lymphocytes have gone through clonal expansion and served the specific immune function for which they were selected, their numbers return to restinct levels.

The role of apoptosis

Malignant cell proliferation and accumulation depend on an imbalance between the rate of cell production and the rate of cell death.R ecent evidence indicates that apoptosis may be important in the development of cancers.

First,apoptosis occurs in the growth and development of several classes of untreated tumour.Examples include murine sarcoma,human basal cell carcinoma and several classes of leukaemia cells grown in culture,including B-cell CLL and childhood acute T-lymphoblastic leukaemia.It has therefore been proposed that apoptosis is involved in the regulation of tumour growth.For example, the removal of cells by apoptosis may explain why some tumours, such as basal cell carcinomas,grow much less rapidly than would be expected from the large number of actively dividing cells they contain.

Recent evidence indicates that inhibition of apoptosis is invloved in the development of follicular B-cell lymphoma,one of the most common forms of low-grade non-Hodgkin's lymphoma(NHL).This condition is often associated with a translocation (an abnormal exchange of genetic material) between chromosomes 14 and 18.This translocation causes abnoraml expression of the gene bcl-2.The presence of this gene is associated with a shorter disease-free survival and failure to achive a complete response to therapphy.

The bcl-2 gene is the best understood of the genes associated with programmed cell death.In cells that over-produce bcl-2,it has been shown that drugs are still able to enter the cell at the usual rate,bind to their specific targets and induce DNA damage.However,since there is no increase in the rate of repair of DNA,the effects of increased bcl-2 expresion,as described in the previous paragraph,are linked to the prevention of apoptosis.

Recent evidence suggests that increased bcl-2 expression confers resistance to chemotherapy in acute lymphoblastic leukaemia(ALL) and some forms of acute myelogenous leukaemia (AML).Exprements in vitro,in which the bcl-2 gene was transferred into various cell lines,have indicated that the bcl-2 gene causes accumulation of lymphoid cells not by prompting cell division,but by inhibiting apoptosis,so that the lifespan of cells is increased.It blocks the endonucleolytic cleavage of DNA that is so characteristic of apoptosis.The accumulation of the lymphoid cells is therefore caused by an imbalance between proliferation and cell death.

In large T-cell cutaneous lymphomas,bcl-2 expression is inversely correlated with the number of apoptic cells seen in response to therapy.The bcl-2 gene may also be involved in the transformation of low-grade lymphomas to more aggressive forms,because accumulation of cells increases the probability of the development of other oncogenes.It therefore seems logical to assume that high levels of bcl-2 expression on tumour cells are predictive of poor disease-free survival.Since bcl-2 staining can be performed in paraffin-embedded material,this could be included in a routine diagnosis for aggressive NHL.Another consideration is that elevated levels of bcl-2 protein after therapy may be a reliable indicator of the probability of relapse.

Interestingly,expression of bcl-2 is 6-25 times higher than growth of in normal cells.However,this is not due to a genetic translocation but to hypomethylation of the bcl-2 gene.This allows escape from the normal cellular regulation and accounts for the growth advantage of the B-CLL cells.This explains why,in B-CLL,as in low-grade lymphomas,which also overexpress bcl-2,B cells accumulate without an increase rate.

Another gene which seems to promote tumour growth and inapproproately prolongs cell survival by inhibiting apoptosis is BCL-ABL.This decrease in cell death seems to be the primary mechanism by which BCR-ABL affects the expansion and eventually dimunance of the Philadelphia-positive chromosome in chronic myelogenous leukaemia,BCR-ABL does not seem to affect cell proliferation.This is similar to the effect seen with bcl-2 in follicular lymphoma.This inhibition of apoptosis could provide the biological explanation for the similarity between two types of malignancy. Recent evidince indicates that BCR-ABL can mimic the modularity signals provided by some cytokines.Not only that,but the cellular factors that regulate apoptosis,so BCR-ABL and bcl-2 could also be involved in the resistance to cytotoxic therapy.