Biomedical Engineering Reference
In-Depth Information
1 Introduction
Despite the well-known clinical importance of metastasis and the involvement
of secondary site tumors in 90% of cancer-related mortality (Jemal et al. 2007),
tumor metastasis is still a mysterious process far from being fully understood
(Chambers et al. 2002; Gupta and Massague 2006; Steeg 2006). As early as the
late nineteenth century, Steven Paget proposed a classic model of metastasis
based on the ''Seed and Soil'' hypothesis that stressed the importance of meta-
static cancer cells and their secondary host organs (Paget 1989). This was
followed by the influential hemodynamic (or mechanical) hypothesis proposed
by James Ewing that placed the blood flow pattern as a main contributor of
organ distribution of cancer metastasis. Today, the era of modern molecular
cell biology and genomics has accelerated the discovery of metastasis genes and
fueled the debates about the origin of metastatic cancer cells (Hynes 2003; Kang
2005; Weigelt et al. 2005b).
Recent insights into the function and characteristics of cancer stem cells
(CSCs) offer a novel approach to understanding the progression of metastasis.
Prevailing excitement about CSCs centers on tumor-generating capability in
serial transplantation experiments and on the ability of CSCs to mediate
chemoresistance. Thus research has focused primarily on the role of CSCs in
primary lesions and has lead to discovery that CSCs can drive tumor formation
in leukemia as well as various solid tumors. While little work has been done to
elucidate the role of CSCs in metastasis, properties of CSCs such as self-renewal
and differentiation make them logical candidates for metastatic colonizers. To
facilitate the discussion of CSCs with different metastatic ability, a distinction
should be made at the beginning of this chapter when referring to two potential
subtypes of CSCs. Primary tumor cancer stem cells (pCSCs) constitute the
original population of tumorigenic cells which initiate formation of the hema-
topoietic and solid tumors and are the center of most CSC research. Metastatic
cancer stem cells (mCSCs) represent a distinct population of cells with the
intrinsic properties to disseminate from the primary site and generate the
distant metastases, the leading cause of most cancer mortality.
2 Acquisition of Metastatic Character During Tumor Development
Tumor growth has long been seen as a Darwinian process on a cellular scale.
This canonical model involves step-wise mutational alterations which confer a
selective advantage and lead to clonal expansion of tumor cells with progres-
sively more pathogenic growth phenotypes (Hanahan andWeinberg 2000). Meta-
static traits, while important in invading surrounding stroma, surviving in the
circulation, and colonizing foreign tissue, seem to offer little or no selective
advantage during early establishment of primary tumors. Thus a puzzle arises
as to how a primary tumor acquires metastatic properties (Bernards and
