Biomedical Engineering Reference
In-Depth Information
transition (EMT) shown to be important in invasion (Scheel et al. 2007). Cells
adjacent to this stroma that are primed to respond through an earlier mutation
may become preferentially metastatic. More evidence is needed to support this
theory, although in pancreatic tumors, EMT is associated specifically with
single cells that leave the invasive front closest to the stroma to invade sur-
rounding tissue (Brabletz et al. 2001). CSCs within this population of activated
cells would have the potential to invade the circulation and exert their tumori-
genic activity in remote organs.
Homogeneity in tumor profiles and association with prognosis cannot
exclude the possibility that a small population of highly metastatic cells exist
which arose late in tumorigenesis and contribute to malignancy and recurrence.
Current microarray profiling techniques are based on total RNA extracts and
unless rare metastatic mutants can be sorted from the remainder of the tumor
mass, they will not be detected by standard means (Hynes 2003). Regardless of
when and how metastatic potential is obtained, understanding the role of
pCSCs in tumor growth and metastasis will offer insight into this important
question.
3 Tumor Subpopulations, Metastatic Origin, and pCSCs
Despite the obvious importance of bulk profiling in characterizing heterogeneous
tumors, it is becoming clear that the majority of cells comprising a tumor actually
may arise through propagation and differentiation of a much smaller subset of
CSCs. The majority of cancer cells in primary tumors and secondary site tumors
lack the capability to initiate new growth as evidenced by the large number of
tumor cells found in cancer patient circulation that result in comparatively small
numbers (and in some cases complete lack) of metastatic growths (Chambers
et al. 2002). In animal models, even when large numbers of tumor cells are
implanted, if these cells do not contain a CSC population, no new tumor
colonization is detected (Gotzmann et al. 2006). However, if pCSCs are indeed
the ''germline'' of the tumor, giving rise to a body of tumor cells, the question
arises as to how these initiating cells are responsible for tumor-wide prognosis
signatures which vary greatly between tumor classes. Owing to the range of
transformations capable of initiating tumor growth and a myriad of microenvir-
onment interactions, a single pCSC could potentially give rise to various tumor
phenotypes depending on oncogenic events sustained early in growth. Some
evidence for this model has been shown in leukemia, though more work is needed
to elucidate the role of early events in tumor-wide metastatic tendencies. It has
been shown that in some leukemias, pre-cancerous CSCs have the ability to
propagate both benign and malignant tumor cells depending on microenviron-
ment factors including immune status of the host and site of injection (Chen et al.
2007). Thus it appears that early challenges to even identical pCSCs can alter later
tumor phenotype and explain the existence of multiple tumor classes.
