The essential features of cancer are uncontrolled growth, overcoming of replicative senescence, invasiveness, and tumor- or organ-specific neoplasm-host interactions. This raises the question whether all cells have the potential to transform into malignant tumors. The physiologic barriers preventing uncontrolled cell division are higher in differentiated cells than in undifferentiated ones. Stem cells have the potential to proliferate, whereas terminally differentiated cells typically have exited the cell division cycle. Stem cells also are not subject to replicative senescence, because they may still express Telomerase, thus preventing the shortening of the chromosome ends with every cell division. In contrast, Telomerase activity is typically absent from differentiated cells. Tumors derived from them would stop growing after a limited number of population doublings. Most importantly, tissue-specific cells would have to redifferentiate in order to adopt the genetic programs for metastasis formation, which are physiologically used for homing by lymphocytes and macrophages, but not by parenchymal cells in solid organs. The association between growth factor signaling and acquisition of invasive-ness is preserved in precursor cells, because it is part of the genetic programs of stress responses. Stem cell expansion and activation are induced by tissue damage. After wounding, there is an accumulation of dividing precursor cells in the affected tissues [Flemming 1885]. Growth factor-dependent signal transduction in precursor cells, but not in differentiated cells, induces transcription factors that activate stress response genes [Witt et al. 2001; Laprise et al. 2002; Nollen and Morimoto 2002]. These characteristics raise the possibility that malignant transformation is not a condition of differentiated cells but rather of tissue-resident precursor cells or stem cells [Sell and Pierce 1994; Reya et al. 2001]. This possibility, referred to as "vitium primae for-mationis,"was alluded to in 1875 in a study of a congenital myosarcoma of the kidneys [Cohnheim 1875]. Alterations in the cellular microenvironment, such as injury or carcinogens, may induce marked differentiative changes in tissue-resident precursor cells. In cancer, this mechanism accounts for the his-tologic appearance of dedifferentiation, in actuality reflecting the accumulation of stem cells that have become unresponsive to physiologic growth control mechanisms. Differentiation is an anticarcinogenic process.
Organs with high turnover of cells, including the epithelium and the lymphohematopoietic system, need a large pool of precursor cells throughout life. The cancer risk in those systems tends to increase with age due to the accumulation of DNA damage over time. In contrast, other organs, including the brain, are subject to low levels of turnover and regeneration in the mature organism. Their pool of precursor cells may decline with age. The cancer risk in those systems peaks in midlife, possibly reflecting a combination of accumulation of DNA damage and decline in the number of susceptible precursor cells. Osteosarcoma has an increasing incidence during adolescence, when the rate of growth of the long bones is highest. During this stage, precursor cell expansion is extensive and predisposes to the risk of malignant transformation. Ovulation may be important in the pathogenesis of ovarian cancer. Proliferation and migration of epithelial precursor cells are required for the repair of defects during ovulation. Hence, ovulatory events could promote tumor progression by stimulating the proliferation of ovarian surface epithelial precursor cells. Consistently, early menarche, late menopause, nulliparity, and the use of fertility-stimulating drugs is associated with increased risk for ovarian carcinoma. In contrast, multiple pregnancies, prolonged breast-feeding, and the use of contraceptives decrease the risk.
The normal mammary gland is composed of three cell lineages, myoepithelial cells that form a basal cell layer, ductal epithelial cells, and milk-producing alveolar cells. They are derived from a common pluripo-tent tissue-resident precursor cell. Although most mammary cells have a limited capacity for self-renewal, these precursor cells can recapitulate the entire functional repertoire of the gland. Mammary cancer risk is positively correlated with the procreative life span of the tissue-resident epithelial stem cells. These cells age prematurely under the influence of TGF-P1, which suppresses Telomerase expression and activity in epithelial cells. Their senescence diminishes the pool of cells that are prone to transformation. Hence, the elevated expression of TGF-P1 in mammary epithelial cells is associated with a reduced susceptibility to cancer [Katakura et al. 1999; Boulanger and Smith 2001]. The EGR-1 (Early Growth Response 1, KROX24, NGFIA, ZIF268) gene product is a transcription factor with roles in differentiation. Its expression markedly reduces growth and tumorigenicity. Conversely, the suppression of egr-1 expression enhances growth and promotes phe-notypic transformation. The growth inhibitory effects of EGR-1 depend on the secretion and autocrine functions of TGF-P, the promoter of which contains two GC-rich EGR-1 binding sites [Liu et al. 1996a].
Epithelial cancers originate from the transformation of precursor cells. Infection with Helicobacter pylori causes chronic gastric inflammation and increases the risk for gastric cancer. The induced chronic inflammation and loss of parietal cells compromise the supply of tissue-resident stem cells. This leads to the repopulation of the stomach with bone marrow-derived precursor cells. In the continued presence of the noxious influence, these recruited precursor cells progress through metaplasia and dyspla-sia to intraepithelial cancer [Houghton et al. 2004].
In keratinocytes and epithelial cells, the levels of P-Catenin correlate with proliferative potential and decreased differentiation. The activation of the WNT
singaling pathway, which P-Catenin is a part of, in epithelial stem cells leads to epithelial cancers [Nusse 1992; Reya et al. 2001]. The disruption of P-Catenin-mediated signals in intestinal cells induces a differentiation program. The control of survivin expression by the P-Catenin pathway may regulate colonic crypt cell renewal and crypt stem cell numbers by preventing stem cell apoptosis in the basal crypt colonocytes. TCF-4 is a transcription factor that normally associates with P-Catenin in response to WNT signaling. Its deficiency causes the rapid exhaustion of undifferentiated progenitors in the crypts of the gut epithelium during fetal development. The total absence of tcf4 causes a lack of stem cells in the small intestine [Watt and Hogan 2000]. Conversely, the activity of P-Catenin and TCF-4 in colorectal cancer is essential to overcome rapid G1 arrest and maintain a genetic program that is physiologically active in the proliferative compartment of colon crypts. The TCF-4 target gene c-myc plays a central role in the switch from proliferation to differentiation by direct repression of the p21CIP1/mF1 promoter. Following a disruption of P-Catenin/TCF-4 activity, the decreased expression of c-MYC releases p21CIP1/WAF1 transcription, which in turn mediates Gj arrest and differentiation. Thus, the P-Catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells [van de Wetering et al. 2002].
Certain molecular markers expressed by cancer cells are shared with precursor cells and may reflect the tumor origin. Brain tumors contain cells expressing the neural stem cell markers CD133 and Nestin while lacking the expression of neural differentiation markers. The proliferation rate of these cells correlates with the clinical aggressiveness of the tumors [Singh et al. 2003].
Specific forms of leukemia arise from mutations in hematopoietic stem cells. Chromosomal translocations that predispose to acute myeloid leukemia arise in hematopoietic stem cells in the bone marrow [Miyamoto et al. 2000]. Clonotypic, leukemia-associated chromosomal rearrangements may also occur in CD34+CD38- stem cells in lymphoid and chronic myeloid leukemias [George et al. 2001; Mauro and Druker 2001], and most acute myeloid leukemia cells have a CD34+CD38- phenotype [Bonnet and Dick 1997].
The precursor nature of the cells of origin for malignancy is evidenced by the frequent expression of fetal proteins in cancer. They include the glycoprotein Carcinoembryonic Antigen (CEA), which may be elevated in gastrointestinal tumors, breast cancer, lung cancer, pancreas cancer, and ovarian cancer, and in cases of bronchogenic carcinoma and mammary carcinoma. Furthermore, CEA is excreted into the urine in papillary carcinoma of the bladder. There are six forms of CEAs. They are related glycoproteins in fetal intestinal epithelium that are expressed only in trace amounts in healthy adults. Another such tumor marker is the glycoprotein a-1-Fetoprotein (AFP), which is elevated in the blood in 60-90% of patients with hepatocellular carcinoma, 60% of patients with teratoid gonadal tumors, and 13% of patients with metastatic liver tumors. It is also expressed by some pancreas carci-nomata and gastrointestinal tumors. Physiologically, a-1-Fetoprotein is synthesized at high levels in fetal hepatocytes and plasma, but in barely detectable amounts in the adult liver. An isoenzyme of Alkaline Phosphatase (Regan enzyme) has anti-genic and biochemical properties that are identical to those of the normal human placenta. This enzyme is present in very low abundance in normal serum, but in 3- to 300-fold increased amounts in about 12% of patients with various forms of cancer.
An oncofetal protein is TAG-72 (Tumor Associated Glycoprotein 72).
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