Normal human diploid cells have a finite potential for proliferative growth.  Thus, as the aging process occurs, the capacity of cells to proliferate gradually diminishes.  The loss of cellular proliferative capacity of cells in culture is termed "senescence," and is the in vitro analog of aging (Hayflick, L. et al.,  Exper.  Cell Res.  25:585 (1961); Hayflick, L. et al.,  Exper.  Cell Res.  37:614-636 (1965); Norwood, T. H. et al.,  In: Handbook of the Biology of Aging (2nd ed.),  Finch, C. E. et al. ( eds.)  Van Nostrand, New York pp.  291-311 (1985); Goldstein, S., Science 249:1129-1133 (1990); Smith, J. R., Monogr.  Devel.  Biol.  17:193-208 (1984); Smith, J. R. et al.  Exper.  Gerontol.  24:377-381 (1989), all herein incorporated by reference).  Experimental evidence suggests that the age-dependent loss of proliferative potential may be the function of a genetic program (Orgel, L. E., Proc.  Natl.  Acad.  Sci. ( U.S.A.) 49:517 (1963); De Mars, R. et al.,  Human Genet.  16:87 (1972); Buchwald, M., Mutat.  Res.  44:401 (1977); Martin, G. M. et al.,  Amer.  J. Pathol.  74:137 (1974); Smith, J. R. et al.,  Mech.  Age.  Dev.  13:387 (1980); Kirkwood, T. B. L. et al.,  Theor.  Biol.  53:481 (1975). 
Indeed, the onset of senescence and aging are accompanied by significant changes in the profile of genes that are expressed.  Through an analysis of such changes, researchers have identified unique mRNAs that are amplified in senescent cells in vitro (West, M. D. et al.,  Exper.  Cell Res.  184:138 (1989); Giordano, T. et al.,  Exper.  Cell Res.  185:399-406 (1989); Lumpkin, C. K. et al.,  Science 232:393-395 (1986)), thus suggesting that cellular senescence is mediated by an inhibitor of DNA synthesis (Spiering, A. I. et al.,  Exper.  Cell Res.  179:159-167 (1988); Pereira-Smith, O. M. et al.,  Exper.  Cell Res.  160:297-306 (1985); Drescher-Lincoln, C. K. et al.,  Exper.  Cell Res.  153:208-217 (1984); Drescher-Lincoln, C. K. et al.,  Exper.  Cell Res.  144:455-462 (1983)).  The recognition of such changes has prompted efforts to clone the genes that encode the factors that control cellular senescence and proliferative capacity (Kleinsek, D. A., Age 12:55-60 (1989); Sierra, F. et al.,  Molec.  Cell.  Biol.  9:5610-5616 (1989); Pereira-Smith, O. M. et al.,  J Cell.  Biochem. ( Suppl.0 (12 part A)) 193 (1988); Kleinsek, D. A., Smith, J. R., Age 10:125 (1987)).  Smith, J. R. (PCT Patent Appln.  Publication No.  WO 93/12251) describes senescent cell derived inhibitors of DNA synthesis. 
Although the proliferative capacity of a cell is believed to be carefully regulated, cells can, through mutation or viral infection, lose their ability to respond to such regulatory factors and thereby re-acquire a capacity to proliferate.  For cells cultured in vitro, this process is referred to as immortalization.  In vivo, such uncontrolled cellular proliferation is a defining characteristic of cancer. 
I. The Complementation Groups of Tumor Cells
Insight into the control of cellular proliferation has been gained from studies in which normal and immortal cells have been fused to form heterokaryons.  Such studies have demonstrated that the quiescent phenotype of a normal cell is dominant over the proliferative phenotype of an immortalized carcinoma cell of a immortalized transformed cell (Bunn, C. L. et al.,  Exper.  Cell Res.  127:385-396 (1985); Pereira-Smith, O. M. et al.,  Somat.  Cell Genet.  7:411-421 (1981); Pereira-Smith, O. M. et al.,  Science 221:964-966 (1983); Muggleton-Harris, A. et al.,  Somat.  Cell Genet.  6:689-698 (1980)). 
Normal diploid somatic cells undergo a limited number of population doublings in culture (Cristofalo, V. J. et al.,  Exp.  Cell Res.  76:419-427 (1973); Goldstein, S., Science 249:1129-1133 (1990); Hayflick, L., Mutat.  Res.  256:69-80 (1991)) in contrast to tumor derived cells which can proliferate unabated.  The former are widely accepted as a model for aging at the cellular level (Hayflick, L., Mutat.  Res.  256:69-80 (1991); Schneider, E. L. et al.,  Proc.  Natl.  Acad.  Sci.  USA 73:3584-3588 (1976)) and the latter of a system which accepted as a model for aging at the cellular level and the latter offer a system which can be exploited to investigate the mechanisms that limit cell division potential and those that permit unlimited cell division.  There have been many studies documenting the cellular changes that accompany senescence (Harley, C. B., Mutat Res.  256:271-282 (1991); Holiday, R., J. Gerontol Biol.  Sci.  45:B36-41 (1990); Macieira-Coelho, A., Mutat.  Res.  256:81-104 (1991); Sherwood, S. W. et al.,  Proc.  Natl.  Acad.  Sci.  USA 85:9086-9090 (1989)). 
Theories as to the molecular mechanisms underlying senescence fall into two broad categories depending on whether their authors consider that senescence is caused by (i) random accumulation of errors in macromolecules or (ii) genetically programmed processes.  Much evidence has been accumulated in favor of a normal genetic program being responsible for expression of the senescent phenotype.  Its converse, immortalization, is an essential step in the full transformation of cells to tumorigenicity (O'Brien, W. et al.,  Proc.  Natl.  Acad.  Sci.  USA 83:8659-8663 (1986)) and in fact it has been proposed that cellular senescence is a mechanism for tumor suppression in human cells (Sager, R., Science 246:1406-1412 (1989)).  Hybrids obtained from the fusion of normal cells with immortal cells have limited division potential (Bunn, C. L., et al.,  Exper.  Cell Res.  127:385-396 (1980); Pereira-Smith, O. M. et al.,  Science 221:964-966 (1983); Muggleton-Harris, A. et al.,  Somat.  Cell Genet.  6:689-698 (1980)) indicating that the phenotype of cellular senescence is dominant and immortality results from recessive changes in normal regulatory genes.  Further, fusion of different immortal human cells with each other yields in some case hybrids which exhibit limited division potential while the fusion of other pairs of immortal cells yields immortal hybrids (Pereira-Smith, O. M. et al.,  Science 221:964-966 (1983)).  Such complementation assays have led to the assignment of 30 immortal human cell lines to four complementation groups (Ning, Y. et al.,  Mutat Res.  256:303-310 (1991); Pereira-Smith, O. M. et al.,  Proc.  Natl.  Acad.  Sci.  USA 85: 6042-6046 (1988)).  Microcell mediated chromosome transfer studies have defined chromosomes 1 and 4 as carriers of senescence genes; the nature and the function of these genes remains to be defined (Ning, Y. et al.,  Proc.  Natl.  Acad.  Sci.  USA 88:5635-5639 (1991)). 
Pereira-Smith, O. M. et al.  demonstrated that pairwise fusions between different immortalized cells occasionally resulted in hybrids that had lost their capacity to proliferate (Pereira-Smith, O. M. et al.,  Proc.  Natl.  Acad.  Sci. ( U.S.A.) 85:6042-6046 (1988)).  By systematically conducting a pairwise analysis, four complementation groups were identified (A, B, C, and D).  The fusion of cells having the same complementation group created hybrids that maintained the immortalized character of the parental cells.  In contrast, when immortalized cells of different complementation groups were fused, the normal genes of one parent "complemented" the deficient mutant genes of the other, and the resulting hybrids became senescent.  This discovery suggested the possibility that a small number of undefined and unidentified genes or pathways might control the ability of a cell to proliferate (Pereira-Smith, O. M. et al.,  Proc.  Natl.  Acad.  Sci. ( U.S.A.) 85:6042-6046 (1988)). 
A capacity to readily determine the complementation group of a tumor cell would provide a valuable means for assessing the severity of the disease, and thus aid in determining the aggressiveness that must be used to treat the cancer.  Moreover, a sensitive means for discerning tumor cells in micro-tumors, or for determining whether a tumor contains different classes of tumor cells would greatly be of great assistance in the diagnosis and treatment of cancer.  The present invention provides such methods.