Similar to their normal tissue stem cell counterpart, cancers have been shown to contain a subset of so called cancer stem cells (or tumor initiating cells) that have the unique ability to perpetuate tumor growth and heterogeneity in serial transplantation experiments. Initially identified in leukemia, they have been subsequently described in a variety of solid cancers like glioblastoma, breast, colorectal, liver, prostate, and pancreatic cancer. CSCs are often rare within the tumor cell mass and, in addition, notoriously resistant against chemotherapeutic agents as well as radiotherapy. Accordingly, CSCs are thought to be the main cause of recurrence, even many years after patients were clinically staged as tumor-free. For example in breast cancer, recent results have demonstrated the important role of CSCs for metastatic spread which is still the main cause of cancer related deaths. It is now well accepted that future therapy will have to consider this cancer cell subpopulation and, indeed, first attempts to specifically target CSCs have shown promising results.
Retinoic acid induced differentiation therapy can specifically target
colon cancer stem cells to prevent disease progression and metastasis
While most cancer therapies target cell proliferation or aim to trigger cancer cell death, only few anti-cancer drugs work by altering the phenotype of cancer cells. Given the importance of cancer stem cells for tumor formation, block of the stemness program for example by inducible differentiation of stem cells may be an promising alternative. We have now identified a transcription factor of the Hox family as an important regulator of intestinal differentiation promoting exit from the stem cell state. This Hox function can be observed not only in primary, normal intestinal stem and progenitor cells in vivo but also in intestinal cancer cells where it causes depletion of cells with cancer stem cell activity. The Hox transcription factor mediates its effect at least in part by repressing the Wnt signaling pathway which represents one major driving force for the intestinal stem cell phenotype and for cancer initiation. Wnt signaling effectuates a reciprocal suppression of Hox and consequently, Hox expression is diminished in colon cancer. Enforced Hox expression interferes with cancerogenesis in vivo by ablating the cancer stem cell phenotype essential for tumor initiation and metastatic colonization. Tumor regression by Hox induction can be triggered by retinoids, which represents a tangible means to treat colon cancer by eliminating cancer stem cells. This suggests that cancer cell differentiation therapy should be re-evaluated for certain cancer types in order to eliminate the driving force of tumors – the CSC population.