Biomedical Engineering Reference
In-Depth Information
extracellular matrix are both common changes in cancer cells in the progression
toward metastasis. In light of the CSC hypothesis, especially the discovery of
specific mCSCs, identifying similar interactions between normal adult stem
cells and their microenvironment becomes crucial. Given the close relationship
between adult stem cells and CSCs discussed above, it is likely that mCSCs
associate with existing cellular niches and utilize them in migration and coloni-
zation. A stem cell niche is a supportive microenvironment providing physical
attachment and environmental signals important to the growth and regulation
of adult stem cells (Schofield 1978). Niches have been extensively characterized
in model organisms such as Caenorhabditis elegans and in the Drosophila germ-
line. In mammals, stem cell niches have been studied in intestine, bone marrow,
skin/hair follicles, the neural system, and the testis (Scadden 2006). While these
microenvironments differ from tissue to tissue, across types there are conserved
themes and signaling pathways important to supporting stem cells. Signal
molecules found in niches that regulate normal adult stem cells such as the
Wnts and TGFb are also known to affect tumor growth and metastasis (Li and
Neaves 2006). Since the same physical space of the niche could be supportive of
both normal stem cells and CSCs, the possibility of competition arises. If the
neo-plasticity and oncogenic modifications found in CSCs offer a survival
advantage, they could potentially displace normal stem cells to take over the
supportive niche. Crowding out normal stem cells could occur during initiation
of primary tumors, but could also be important in the establishment of mCSCs
in distant organs. In fact, in osteolytic bone metastasis, it has been shown that
endosteal osteoclasts become activated (Guise et al. 2006) which can induce the
mobilization of hematopoietic progenitor cells within the bone marrow (Kollet
et al. 2006).
In breast cancer, where bone marrow is the most common site of metastasis,
much evidence points to specific interactions between mCSCs and endogenous
stem cell niches. Aside from providing regulation through signaling, niches also
serve as anchoring sites for stem cells. Hematopoietic stem cells are attached to
osteoblastic niches via N-cadherin/b-catenin complexes (Calvi et al. 2003)
regulated upstream by Wnt signaling. The adhesive qualities and population
size of HSCs are determined by the glycoprotein Osteopontin (Opn) which is
also important in metastasis of breast cancer (Furger et al. 2001; Kang et al.
2003; Stier et al. 2005) implying a role for Opn in mCSC regulation. HSCs also
require a calcium-sensing receptor (CaR) to properly localize to bone marrow
niches (Adams et al. 2006). Overexpression of CaR in breast cancer tumors
correlates strongly with bone metastasis potentially allowing mCSCs to prefer-
entially localize and colonize endosteal stem cell environments (Adams et al.
2006; Mihai et al. 2006).
In addition to taking over defined niches, tumor cells could also manipulate
nearby niches to favor growth of oncogenic CSCs. This phenomenon has been
observed in basal cell carcinomas (BCCs). Bone Morphogenic Proteins (BMPs)
are known to promote stem cell differentiation leading to exit of the stem cell
niche and their action is inhibited by the secreted factor Gremlin 1. Tumor cells
