* Introduction - An Overview of our research
* Significance - How our research is useful
* Future - Questions arising from our research
We are currently interested in several topics that have arisen from the analysis of a tumor-resistant mouse strain. We showed that mice with a null mutation in syndecan-1 (Sdc1; a cell surface heparan sulfate proteoglycan) were resistant to mammary tumors when crossed to a strain that is a breast cancer tumor model (Alexander et al, 2000). This mouse strain expresses the oncogene Wnt1 under the control of a mouse mammary gland-specific promoter (a viral DNA sequence, MMTV-LTR). When this genetic interaction was reconstructed in vitro in a culture model, we found that Sdc1 did not affect the Wnt signaling pathway directly but redirected the development of the mammary gland to create a Wnt-insensitive mammary epithelial cell population (Liu et al 2003). Further analysis of mammary gland development in Wnt-induced mice suggested that Wnt signaling promoted an increase in the progenitor/stem cell fraction and that this change in the poulation demographic was key to Wnt-induced tumor initiation. By means we do not yet understand, in the absence of Sdc1 the progenitor/stem cell fraction is deficient. The Sdc1-/- mutation therefore opposes the tumor initiation event induced by Wnt signaling (Liu et al 2004).
Wnt signaling is highly oncogenic for human epithelia: for example, the second most prevalent human tumor type, colorectal cancers, are almost all initiated by mutations that activate the Wnt signaling pathway (Bienz and Clevers 2000). Similar mutations induce a significant number of other epithelial and neuroepithelial tumors (Polakis 2000). The normal function of this pathway in mammals is thought to be the regulation of development and organogenesis. How can this normal role be subverted to cause cancer?
A clue to the mechanism that underlies the oncogenicity of ectopic Wnt signaling has been gleaned from the reciprocal effects of loss and gain of function Wnt signaling mutations on morphologic compartments thought to contain somatic stem cells. Thus for intestine, skin and the hematopoietic lineages, loss of Wnt signaling eliminates the stem cell compartment, whereas gain of Wnt signaling induces stem cell hyperplasia (Reya et al 2001).
The majority of cells in adult epithelia are thought to have a limited intrinsic
division potential. They are the daughters of a minor population of progenitor
cells that are relatively undifferentiated and long-lived (or immortal). This
longevity is thought to facilitate the accumulation of genetic mutations and
transformation, and to make them candidate tumor precursor cells (Potten
et al 2003). However, it is thought that stem cells are usually well guarded
against mutagenic changes. It therefore becomes important to understand why
(at least in this case) the activation of stem cells carries such a high risk
of tumor development.
Another group has shown that breast tumors contain a minor subpopulation
of stem cells that is responsible for tumor growth (Al-Hajj
et al 2003). These share at least some of the properties of normal stem
cells, although the cellular origin of the tumor stem cell is unknown (Dick
2003). Mammary stem cells will likely share some gene expression signatures
with other stem cell types. These will distinguish them from the differentiated
cell majority, and may constitute a viable therapeutic target.
We have shown that Wnt signaling induces an increase in mammary progenitor fraction, and that the absence of Sdc1 decreases this fraction. We propose that there will be many such factors that affect stem cells specifically, and that these factors will modify the risk of tumor development for humans. It is key to understand how somatic stem cells are regulated in order to estimate this risk.
We thank our funding sources: the National Cancer Institute, the Susan Komen Breast Cancer Foundation and the Breast Cancer Research Program.
1. What is the tumor precursor cell in Wnt-induced tumors? Why is it so
susceptible to neoplastic transformation?
2. What changes occur in the population demographics of mammary epithelial
cells in Sdc1-/- mice?
3. What normally controls stem cell fraction in mammary gland? Is stem cell
growth regulated by differentiated cells?
4. How are Sdc1-/- mammary epithelial cells resistant to oncogenic canonical
Wnt effectors?
5. What are the characteristics of mammary stem cells?
6. Why is an intracellular Wnt signaling effector a much less potent oncogene
than extracellular effectors?
7. How does Sdc1 promote stem cell growth and survival?
8. We know now that Sdc1-/- mammary cells are not deficient in heparan sulfate;
there are compensatory changes in other GAGs. What is the effect of a true
Sdc1 deficiency on mammary gland development?