Metastasis and stem cell pathways

Abstract

Recent studies have described a small population of self-renewing and multipotent cells within tumors termed "cancer stem cells." These cells share many traits with somatic and embryonic stem cells and are thought to be responsible for driving tumor progression in a growing list of neoplastic diseases. Cells within solid tumors encounter hypoxia due to poor vascular function. Both long-standing and emerging data describe hypoxic effects on somatic and embryonic stem cells, and it is likely that hypoxia also has profound effects on cancer stem cells. These effects include the activation of pathways that induce the dedifferentiation of cancer cells, the maintenance of stem cell identity, and increased metastatic potential. Hypoxia may contribute to tumor progression by specifically impacting these pathways in cancer stem cells.

Figure 1

HIF activation in cancer stem cells. Hypoxic exposure within tumors results in the stabilization of HIF-1α and HIF-2α. Increased HIF activity results in the activation of pathways involved in maintaining stem cell identity. HIF-1α can stabilize Notch1, which maintains the undifferentiated state. HIF-1α also induces genes important for invasive and metastatic phenotypes, including lysyl oxidase (LOX) and matrix metalloproteases (MMP). HIF-2α stabilization induces the expression of Oct-4, one of the most important stem cell maintenance factors. HIF-2α also enhances the activity of c-Myc, which enhances proliferation and is also required for stem cell maintenance. Thus, through HIF, hypoxia activates several pathways important for stem cell maintenance. These pathways in turn impact processes such as proliferation, decreased differentiation, invasiveness and metastasis.

Figure 2

Hypoxic effects on the generation and maintenance of cancer stem cells. Possible mechanisms for the generation and maintenance of cancer stem cells and the role of hypoxia are depicted here. A. Hypoxic exposure activates pathways that ultimately lead to dedifferentiation of a differentiated cell. These include for example, activation of the Notch1 pathway, induction of Oct-4 expression, enhancement of c-Myc activity, ID2 induction (in neuroblastoma), among other alterations. B. Cancer stem cells exposed to hypoxia maintain their stem cell identity by inducing important stem-cell promoting pathways. C. Low O₂ increases metastasis in cancer stem cells by reducing E-cadherin levels and increasing pro-metastatic genes such as LOX, MET, and proteases (such as MMP and uPAR). These pathways are regulated by HIF expression. Once the cancer stem cell has left the primary tumor, it colonizes other organs, a process also impacted by hypoxia (see text for details).