K S Ratnakar, MD*

Apoptosis, otherwise called as programmed cell death, received unprecedented attention in the last decade. The morphological and molecular events are defined and identified1. From organogenesis to oncogenesis, apoptosis has been considered to play a pivotal role. The programme is molecular involving a class of genes belonging to bcl2 family. Recently, an interesting group of a family of proteins called Inhibitors  of Apoptosis (IAPs) are characterized. They have a unique capacity to abort the suicidal attempts of cells due to various insults, from microbial to environmental2. These proteins are known to ‘block’ apoptosis and one of them christened as ‘SURVIVIN’ has been characterized in mammalian cells. The overexpression of ‘survivin’ in malignancies indicated its role in allowing the cells to multiply while effectively blocking cell death mechanisms.

Human “survivin has been sequenced with complete mapping of its 14,796 nucleotides and is located at telomeric position of chromosome 17, Q25 comprising 14.7 kb occupying 3% of distance from the telomere3. The genome encodes 142 aminoacids of the proteins of “survivin”. The organization patterns of human and other mammalian (mouse) “survivin” and sequence analysis is now currently available4.  “Survivin” gene expression is unique, by not involving TNF alpha signaling.

Using appropriate techniques such as northern hybridization,  ‘survivin’ bands are conspicuously absent in normal adult human tissues2. This contrasts several IAPs with different levels of expression normally in the physiological proliferating  compartments such as intestinal epithelium, basal cell layer of epidermis which are negative for “survivin”. However, in foetal life (14-21 wks) the ‘survivin’ expression is abundant. This differential expression of survivin in adult visa-vis foetal tissues is unique and important in understanding neoplastic processes.

Recent studies confirmed over expression of ‘survivin’ in several human neoplasms. Solid organ malignancies, of lung, colon, breast, pancreas and haematological malignancies including lymphomas, strongly overexpress ‘survivin’2. Curiously, the adjacent normal tissues are not stained for ‘survivin’. However, the percentage of cells expressing survivin by immunohistochemical stains varies from 30% in gastric cancer5 to 100% in malignant melanoma cells6. The staining is predominantly

cytoplasmic. More sensitive techniques using high affinity antibodies, than conventional   immunohistochemistry, yielded 100% positivity for survivin in malignant cells. The intense staining noticed in cells under mitosis suggest mitotic cycle preservation.

Oncobiologists and pathologists seek answers to two important questions, namely, what is the survivin expression pattern in preneoplastic lesions? does survivin expression, carry any predictive value on prognosis?  While preneoplastic conditions undoubtedly express the protein ‘survivin’, what determines full blown expression in infiltrating lesions that subsequently  develop is largerly elusive. The hypothesis proposed is based on the studies on the neuroblastoma, Hela cell lines include, transcriptional reactivation. The prognostic role of ‘survivin’ has been definitely appreciated in several malignancies from the studies so far available. Retrospective histological studies recorded, consistent overexpression of ‘survivin’7 as a  rule in all the aggressive high grade lesions. Corroborative invitro studies revealed inhibition of apoptosis in these cells8.

The evolutionary role of ‘survivin’, in terms of organogenesis, cell cycle, is being explored currently with several interesting findings which have therapeutic implications in malignancies in the years to come. Effective inhibition of apoptotic stimuli (Fas stimulation , TNF   alpha / cycloheximide)9 and caspase related abolition of apoptosis by ‘survivin’, has been characteristically observed in situations of overexpression only.  These observations help onocologists to view ‘survivin’ as protein of future, both in understanding and management of neoplastic processes.
 

REFERENCES

1. Adams JM, Cory S. The Bcl-2 protein fairmly. Anbiters of cell survival. Science 1998; 281;1322 –26.
2. Ambrosini G, Adida C, Altieri DC.  A novel anti-Apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997;3:917 –21.
3. Abrosini G, Adida C, Sirugo G, et al.  Induction of apoptosis and inhibition of cell proliferation by survivin Gene tangetrig. J Biol Chem 1998; 273;11177-82.
4. Lif, Altieri DC. The cancer anti-apoptosis mouse Survivin gene: characterization of locus and transcriptional requirements of basal and cell cycle dependent expression.  Cancer Res 1999;59:3143-51.
5. Lu CD, Altieri DC,  Tanigalia N. Expression of a Novel apoptosis gene, survivin, correlated with tumor cell Apoptosis and p53 accumulation in gastric carcinomas.  Cancer Res 1998;58:1808-12.
6. Grossman D, McNiff  JM, LIF, et al. Expression and target of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermotol 1999 [ in press].
7. Adida C, Berrebi D, Peuchmaur M, et al. Antiapoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 1998; 351: 882-3.
8. Tamm I, Wang Y, Sausuille E, et al.  IAP- family protein survivin inhibits
      caspase activity, and apoptosis induced Fas (CD 95), BAX, caspases and
       anticancer drugs. Cancer Res 1998;58:5315-20.
9. Deyeraux QL, Reed JC. IAP fairly proteins – Suppressors of apoptosis. Genes Dev 1999;13:239-52.