Differentiation Tumor versus Normal Cells

Embryonic development and metastasizing tumors are characterized by parallel processes of invasion, migration, and colonization so that cancer cells can be considered to behave as undifferentiated or inappropriately differentiated embryonic cells. Probably the best example to illustrate this point is the highly malignant teratocarcinoma tumors that contain a variety of differentiated tissues, including muscle, bone, teeth, and hair, showing an erroneous execution of the development program.125

There are two hypotheses that could explain why a cancer cell lacks all the features of a fully differentiated cell. First, the development process may have been stopped at some point. This seems to be the case for some hematological malignancies such as acute promyelocytic leukemia.126 For this special type of leukemia, therapies using all-trans retinoic acid are particularly efficacious due to the ability of the drug to resume the differentiation program of the tumor cells.127 Second, and this may apply more generally to solid tumors, cancer cells may have undergo dedifferentiation, which does not lead to a more primitive cell type, but to a new, nonstandard, and abnormal cell type. Probably the best example of this is in colorectal cancers. Inactivation of the tumor suppressor gene APC is the most important event for sporadic initiation of colorectal cancers and progression toward adenocarcinoma.128 APC mutations were found to cause dysplasia, and this change in cell character is critical for initiation of colorectal cancers.129 Moreover, spontaneous tumors in APC knockout mice were formed by cells retaining crypt-cell-like features instead of continuing their differentiation.130 The biochemical function of the APC protein is to downregulate beta-catenin levels to reduce the transcription activity of the TCF4/beta-catenin complex.131 Abrogation of TCF4 expression in mice results in early lethality, due to a complete absence of stem cells of the gut.132 Beta-catenin/TCF4 signaling seems to be necessary for the maintenance of the stem cell population, and one of the main functions of APC is to control the transition of stem cell to daughter. Last but not least, it was recently shown that epigenetic changes in specific gene promoters alter the balance of differentiated versus undifferentiated cells. The loss of imprinting in the IGF-2 gene is present in about 30% of patients with colorectal cancer. Reconstitution of this loss of imprinting in heterozygous APC+/ _ mice resulted in a higher incidence (twofold) of intestinal tumors. The heterozygous animals also showed a shift toward a less differentiated normal intestinal epithelium.133

It is also important to mention that a lack of differentiation of nontumor cells may contribute to tumor growth. Thus, a defective host antitumor immune response is an important mechanism allowing tumor cells to evade the control of the immune system. Induction of an effective antitumor response requires the active participation of host bone-marrow-derived antigen presenting cells (APCs). Dendritic cells are the most potent APCs, and those cells are sometimes defective in cancer patients due to a fault in their maturation (e.g., lack of expression of costimulatory molecules). Different factors are at the origin of defective DC differentiation, including cytokines and angiogenic factors.134 However, the link between production of those factors and tumor growth remains to be elucidated.

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