On the stem cell origin of cancer

Abstract

In each major theory of the origin of cancer-field theory, chemical carcinogenesis, infection, mutation, or epigenetic change-the tissue stem cell is involved in the generation of cancer. Although the cancer type is identified by the more highly differentiated cells in the cancer cell lineage or hierarchy (transit-amplifying cells), the property of malignancy and the molecular lesion of the cancer exist in the cancer stem cell. In the case of teratocarcinomas, normal germinal stem cells have the potential to become cancers if placed in an environment that allows expression of the cancer phenotype (field theory). In cancers due to chemically induced mutations, viral infections, somatic and inherited mutations, or epigenetic changes, the molecular lesion or infection usually first occurs in the tissue stem cells. Cancer stem cells then give rise to transit-amplifying cells and terminally differentiated cells, similar to what happens in normal tissue renewal. However, the major difference between cancer growth and normal tissue renewal is that whereas normal transit amplifying cells usually differentiate and die, at various levels of differentiation, the cancer transit-amplifying cells fail to differentiate normally and instead accumulate (ie, they undergo maturation arrest), resulting in cancer growth.

Figure 1

Features of a testicular teratocarcinoma. A: Gross picture of a testicular teratocarcinoma. B: Selected histological section showing mature bone marrow (bm), connective tissue (ct), and squamous epithelium producing keratin (k). C: Immunoperoxidase staining for AFP in yolk sac element (arrow). D: Immunoperoxidase staining for CGH in placental element (arrow). E: Embryoid body. F: Hierarchical model of germinal cell tumors. Depicted are the stages of maturation of germ cells at which maturation arrest results in germinal stem cell derived cancers. Embryonal carcinoma is a cancer of totipotent germinal stem cells. Choriocarcinoma, yolk sac carcinomas, and teratomas are derived from embryonal cell carcinomas and most teratocarcinomas contain mixtures of these cell types. Seminomas express the spermatocytic phenotype, which represents a further stage of differentiation.

Figure 2

Preneoplastic lesions in experimental chemical hepatocarcinogenesis. A: Gross appearance of liver nodules induced by cyclic administration of AAF in a rat; normal liver on left, nodular liver on right. B: Microscopic picture of a liver nodule. C–E: α-Fetoprotein-containing cells during various regimes of chemical hepatocarcinogenesis: C: Cyclic acetylaminofluorene (AAF) (immunofluorescence). D: AAF-partial hepatectomy (Solt-Farber model) (immunoperoxidase). E: Diethylnitrosamine (DEN) (immunoperoxidase). F: Hierarchical model of liver carcinogenesis. The arrows in B point to the edge of a neoplastic nodule in the liver. The arrow in C points to an AFP-containing oval cell; the arrow in D to an AFP positive duct.

Figure 3

A: Hierarchical lineage model of skin cancer. B: Hierarchical lineage model of breast cancer. C: Histological picture of Burkitt’s lymphoma cells showing accumulation of large B cells. D: Effect of Ig promoter in transgenic mice with the Ig promoter linked to c-myc and bcl-2. Although all of the cells in the transgenic mice have the translocation, including the hematopoietic stem cells, the Ig promoter is only activated at the B-cell stage of differentiation. Thus, in this experimental model of Burkitt’s lymphoma, cancer cells accumulate at the B-cell level. E: Stages of maturation arrest of leukemia. The expression of products of gene translocations occurring in stem cells depends on the stage of differentiation of the cells in the myeloid series: bcr/abl is at the myelocyte stage, PML/RARα is at the promyeloid stage and a large number of mutations at the hemocytoblast stage (see text). F: Events during the process of colon carcinogenesis. The first mutation in colon carcinogenesis is APC, absent in polyposis coli. APC normally acts to degrade β-catenin and survivin. When these substances are not degraded they contribute to increased proliferation and decreased cell death allowing the affected cells to accumulate and acquire additional mutations rather than be sloughed off in the lumen.