Biomedical Engineering Reference
In-Depth Information
Tumor promoters can then be thought of as agents that disrupt the tissue and
activate stem cells, while tumor initiators damage DNA and mutate specific
genes. The only difference between the experimental animal models of tumor-
igenesis and the human situation is the fact that human cancers involve a
chronic exposure to tissue-damaging agents and mutagens (Tennant, 1999).
Most of the environmental agents that lead to stem cell activation would be
classified as promoters, non-DNA reactive agents that enhance the tumorigeni-
city of initiators (mutagens). Some environmental agents, such as tobacco
smoke and UV irradiation, contribute to both initiation and promotion as
they stimulate tissue proliferation and damage DNA.
In light of the identification of a small population of cancer stem cells, the
initiation and promotion scheme can be updated. Cancer can be envisioned to
be caused by a combination of agents disrupting tissue architecture and activat-
ing stem cells, and agents that damage and mutate DNA. This paradigm
explains the role of known agents implicated as causing cancer and focuses
the problem on a subset of abnormal cells that could be specifically targeted,
resulting in more effective therapies.
8 The Origins of the Tumor-Initiating Cell
Cancer stem cells can arise from two potential pathways. A multipotent stem cell
with abnormal growth control can give rise to a cancer stem cell (Reya et al.,
2001). Alternatively, a progenitor cell or more committed cell could acquire the
self-renewal capabilities and become a cancer stem cell (Shipitsin and Polyak,
2008). There is evidence for both mechanisms, and some have argued for a
dynamic process within the tumor. Transfection studies where activated onco-
genes can transform murine fibroblasts document that non-stem cells can be
converted into cancer (stem) cells. Evidence has also been found for the fusion of
stem cells with tissue cells, creating cells with self-renewal capacity (Houghton
et al., 2004).
From 2001 to 2008, Robert A. Weinberg and colleagues (Elenbaas et al.,
2001; Ince et al., 2007; Zimonjic et al., 2001) were able to demonstrate that
sequential introduction of three cancer-associated genes into human mammary
epithelial cells (HMECs) renders these cells tumorigenic. Genetic complexity of
breast cancer cells had heretofore made it difficult to identify the specific genetic
alterations that are required for the switch from a normal cell to a tumor cell. In
this work, Weinberg's group first focused on creating a human xenograft
mammary cell model (Kuperwasser et al., 2004) and later on specific gene
transformations using SV40 large-T antigen, telomerase hTERT, and onco-
genic H-rasV12, each of which interfere with essential regulatory pathways
governing cellular growth and survival. Sequential introduction of these three
genes into HMECs results in cells that display the typical properties of malig-
nant cells in culture, and form aggressive tumors when transplanted into mice.
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