Controlling Factors of Cancer C ell M etabolism
Recent evidence suggest.s that cancer cell m etabolism is a com plex and highly integrated phenom ena and a better understanding of its controlling factors can provide a rationale for the gene therapy, m olecular and m etabolic therapy of can cer (1-2 ). Carcinogenesis in hum ans and laboratory anim als is a com plex, m ultistep process and m ay result from the action of any one or a com bination of chem ical, physical, biologic, and genetic insults to cells. Thus, heredity (genetic factors) and environm ent (epigenetic factors) both operate in the origin of cancer. D om inantly heritable cancer is caused by "cancer genes" that im part high relative risks, but account for only a sm all part of the incidence of cancer; they are usual ly recessive in oncogenes, m utation or loss of the second allele being necessary. O ther genes interact w ith environm ent in carcinogenesis; these m ay im part rel atively sm all risks, but because their frequencies m ay be high and the attributable risks can be great. The process of carcinogenesis m ay be divided into at least three stages: initiation, prom otion, and progression. The first stage of carcinogenesis, initiation, results from irreversible genetic alteration, such as one or m ore sim ple m utations, transversions, transitions, or sm all deletions in DNA. The reversible stage of prom otion does not involve changes in the structure of D NA's but rather in the expression of the genom e and the final irreversible stage of progression is characterized by karyotypic instability and m alignant growth. Critical m olecular targets during the stages of carcinogenesis include proto-oncogenes, oncogenes, and tum or suppressor genes (or anti-oncogenes). O ncogenes and anti-oncogenes play central roles in carcinogenesis and this suggests that all hum an cancers are initiated by genetic or epigenetic changes and there are m ultiple w ays by w hich environm ental (epigenetic) factors and inherited (genetic) factors can operate in the origin of cancer. Cancer is therefore a genetic disease at the level of the cell, and m any of the "cancer genes" have im portant norm al functions in the control of growth and developm ent. The recent identification of Patched, a gene essential for D rosophila em bryonic developm ent, as a tum or suppressor gene has focused attention on the concept that carcinogenesis involves abnorm alities of develop ment. In fact, a large num ber of genes in the signaling pathw ay of the patched gene are either tum or suppressor (anti-oncogenes) or oncogenes. This suggests that growth control and its controlling factors is a critical requirem ent of differen tiation, and that aberrant cellular and m etabolic developm ent can contribute to
carcinogenic process, nam ely the vast m ajority of "sporadic cancers" that have properties of a com plex genetic disease. A pproaches to identify com m on allele in cancer associated genes is prom ising to a better understanding of cancer as w ell as to the rational design of preventive and therapeutic strategies of cancer. A lthough the search for genetic and epigenetic (environm ental cell) factors in can cer cells now occupies a central place in cancer research, but the w ay to solve the riddles of how norm al cells govern their replication and grow th behavior and w hy cancer cells do not, rem ains still open. Thus the characteristic of m olecular and m etabolic alterations that define neoplasia have not been elucidated (1-6 ). Epigenetic or environm ental factors m ay act w ithout, directly, dam aging the structure of the host cell genom e, and they act m ainly in the prom otion and pro gression stage of carcinogenesis, and are also called "prom oting agents" (7). Thus cancer m ay be a m alady of genes, arising from genetic dam age of recessive and dom inant m utations, rearrangem ents of DN A and point m utations, all leading to distortion or either the expressions of biochem ical and m etabolic function of genes. Therefore, as the genom e of the cancer cell is better understood, w e hope to acquire new strategies for the prevention, diagnosis, and therapy of cancer (8 ). D espite the fact that in recent years several genes w ere identified and their possi ble role in etiopathogenesis of cancer w as m entioned, there is no direct evidence that a certain gene is a direct causative factor of certain types of cancer, and in my opinion is better the term "cancer genes" to be replaced by "cancer associated genes" since other concom itant factors should sim ultaneously act on the cell to initiate its m utation to a cancer cell, and the origin of cancer is still m ultifactorial. (Fig. 6 ). Recent studies in m olecular oncology revealed interesting facts, nam ely in addition to pivotal role of proto-oncogenes, cellular oncogenes, and tum or sup pressor genes (or anti-oncogenes), and D N A repair genes, these recent studies revealed the existence of a vast netw ork of signals betw een the cells (extra-cellular signaling pathways) as w ell as w ithin the cells (intra-cytoplasnic or intracellular signals) such as signal transduction system (STS), other signaling intracellular pathw ays (SIP) and transactivation factors. These pathw ays w ithin a cell (intra cellular signals) receive and process growth stim ulatory signals by other cells in a tissue, and such cell-to-cell signaling usually begins when one cell secretes growth factors (GFS), and these proteins m ove through the extra-cellular spaces and bind to specific receptors (G FR's)— "antenna-like" m olecules-on the surface and cell m em branes of neighbor cells. W hen a growth stim ulatory factor attaches to a receptor, the receptor conveys a proliferative signal to proteins in the cytoplasm , and these dow nstream proteins, in turn, em it stim ulatory signals to other proteins in a chain that ends in the nucleus. W ithin the nucleus, proteins know n as tran scription factors respond by activating a cohort of genes that propel the cell through its growth cycle. Thus, these gene-proteins, nam ely gene m etabolic pro teins play a cardinal role in cell growth, cell transform ation and progression. Also, this large netw ork of circuitry of intracellular and extra-cellular signaling path w ays, nam ely signal and transduction pathw ays (STD) play a crucial role in con trolling cell growth and cell-to-cell com m unications. W hen these signaling sys tem s are going "aw ry ", the cell growth and division w ill be deregulated and the cancer arises, and thereby cancer can be conceived as a "cell growth aberration". All this recent data w ill have a param ount significance for carcinogenesis, cancer therapy, and nam ely the design and developm ent of novel anti-cancer drugs
which selectively destroy the cancer cells, w hile sparing the norm al host cells (9, 10). Recently, the potential role of m em bers of the steroid /thyroid nuclear receptor super-fam ily that includes proteins that bind glucocorticoids, estrogens, progestins, androgens, m ineralocorticoids, thyroid horm one, vitam in D, retinoic acid (RA) and possibly digoxin as well as the m echanism by w hich they regulate
gene transcription and their potential role in carcinogenesis. Also the occurrence in various cancers of m utant nuclear receptors such as "w ild " ERs and nuclear receptors w ithout specific ligand "orphans" ER 's w ere found on cancer cells, or the regulation of proto-oncogene expression by nuclear recep tor/horm one com plexes. W ith the elucidation of possible m etabolic protein-protein interactions, of nuclear receptors w ith proto-oncogene derived transcription factors, it w ill be possible to scrutinize the m olecular basis for the nuclear transcription factor func tion in oncogenesis and disease in general. As soon as we possess this know ledge, it w ould be possible to translate into the realm of cancer therapy of certain neo plasm s and design of novel anti-cancer drugs (11-15).