Epigenetics Changes in Cancer Cells

Highlights of the American Association for Cancer Research Special Conference on Chromatin, Chromosomes, and Cancer Epigenetics; November 10-14, 2004; Waikoloa, Hawaii

Kris Novak, PhD

Disclosures
In This Article

Cancer Stem Cells and Gene Derepression

In addition to silencing genes that regulate cell proliferation and cell death, epigenetic modifications are also important regulators of stem cell function. Common cancers (of the breast, colon, and lung) arise in tissues that contain a large subpopulation of proliferating cells that replenish the supply of shorter lived, mature cells. In these organs, cell maturation is arranged in a hierarchy, in which a small population of stem cells gives rise to the large population of mature cells, which make up the bulk of the tissue. These stem cells perpetuate themselves through a process called "self-renewal" -- a cell division in which one or both of the daughter cells remain undifferentiated and retain the ability to give rise to another stem cell that has the same capacity to proliferate as the parent cell. Studies have shown that genes that regulate self-renewal are inactivated throughout differentiation by epigenetic modification, but these self-renewal pathways are reactivated in cancer cells.

Michael Clarke,[5] of the University of Michigan Medical Center, Ann Arbor, Michigan, spoke about the oncogene Bmi-1, which encodes a member of the polycomb family of proteins involved in the epigenetic repression of target genes. Clarke's group showed that adult and fetal mouse and adult human hematopoietic stem cells express Bmi-1. They created Bmi-1-null mice and observed that although the number of hematopoietic stem cells in the fetal livers of these mice was normal, the number was reduced in postnatal Bmi-1-null mice. Transplanted fetal liver and bone marrow cells from Bmi-1-null mice were able to contribute only transiently to hematopoiesis. There was no detectable self-renewal capability of adult hematopoietic stem cells, indicating that this process was defective in Bmi-1-null mice.

Gene-expression analysis revealed that the expression of self-renewal genes, cell-survival genes, transcription factors, and genes that inhibit proliferation (such as p16Ink4 and p19Arf) was altered in bone marrow cells of Bmi-1-null mice. Expression of p16Ink4 and p19Arf in normal hematopoietic stem cells resulted in proliferative arrest and p53-dependent cell death, respectively. So, Bmi-1 appears to repress expression of these genes, through epigenetic mechanisms, to generate the self-renewal capacity of hematopoietic stem cells. Further studies are required to determine how this protein alters chromatin structure to regulate the transcription of genes that mediates the self-renewal capacity of stem cells.

Clarke[5] has also isolated cancer stem cells from breast tumors. Tumors are made up of a heterogeneous population of cells. The researchers separated human breast tumor cells, based on cell-specific, cell-surface markers, to determine the ability of different populations to reform tumors when injected into immunocompromised mice. They found that only a small population of tumor cells has the capacity to initiate tumor formation in mice -- and these are believed to be breast cancer stem cells. Only about 1% to 3% of human breast tumor cells seem to have this capacity, and only about 500 of these cells need to be injected to form tumors. Injecting even tens of thousands of other tumor cell types does not lead to tumor development in mice.[5] Further characterization of these cells will provide important information about the features of breast cancer stem cells and determine whether these cells may represent critical therapeutic targets.

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