Microtubule-associated kinase DCAMKL-1 a novel target for anti-CSC-based strategies?

Scientists discover stem cell protein linked to cancer growth, Kerentech, May 23, 2009. Excerpt:

Researchers have studied stem cell proteins for years, but Houchen and Anant said they not only found a new cancer protein, but discovered how the protein works to turn off a natural tumor suppressor and turn on a cancer-causing gene.

The results of their research will be published in an upcoming issue of the journal Gastroenterology.

See also: Scientists Discover How Cancer Protein Works, News release, OU Cancer Institute. Excerpt:

The latest work involves a new stem cell protein. Houchen and Anant discovered that this protein was responsible for regulating a natural tumor suppressor. It is the first such evidence of a stem cell protein regulating a tumor suppressor. When the protein, which is found in cancer, was increased, it caused the tumor suppressor to go down and the tumor grew in research models. When the protein was reduced or "knocked down," the level of tumor suppressor went up and the tumor stopped growing. Scientists also found that when they stopped the protein, the expression of a cancer-causing gene also went down.

The relevant publication is: Selective Blockade of DCAMKL-1 Results in Tumor Growth Arrest by a Let-7a MicroRNA-Dependent Mechanism by Sripathi M Sureban and 6 co-authors, including Shrikant Anant and Courtney W Houchen, Gastroenterology 2009(May 12) [PubMed Citation].

Another related publication from this group: Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice by Randal May and 5 co-authors, Stem Cells 2008(Mar); 26(3): 630-7 [Epub 2007 Nov 29]. [PubMed Citation][Full text is publicly accessible (via Gratis OA)].

c-Myc required for maintenance of glioma CSC

c-Myc is required for maintenance of glioma cancer stem cells by Jialiang Wang and 7 co-authors, including Jeremy N Rich, PLoS ONE 2008(Nov 20); 3(11): e3769. [PMCID: PMC2582454]. Abstract:

Background

Malignant gliomas rank among the most lethal cancers. Gliomas display a striking cellular heterogeneity with a hierarchy of differentiation states. Recent studies support the existence of cancer stem cells in gliomas that are functionally defined by their capacity for extensive self-renewal and formation of secondary tumors that phenocopy the original tumors. As the c-Myc oncoprotein has recognized roles in normal stem cell biology, we hypothesized that c-Myc may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells.

Methodology/Principal Findings

Based on previous methods that we and others have employed, tumor cell populations were enriched or depleted for cancer stem cells using the stem cell marker CD133 (Prominin-1). We characterized c-Myc expression in matched tumor cell populations using real time PCR, immunoblotting, immunofluorescence and flow cytometry. Here we report that c-Myc is highly expressed in glioma cancer stem cells relative to non-stem glioma cells. To interrogate the significance of c-Myc expression in glioma cancer stem cells, we targeted its expression using lentivirally transduced short hairpin RNA (shRNA). Knockdown of c-Myc in glioma cancer stem cells reduced proliferation with concomitant cell cycle arrest in the G0/G1 phase and increased apoptosis. Non-stem glioma cells displayed limited dependence on c-Myc expression for survival and proliferation. Further, glioma cancer stem cells with decreased c-Myc levels failed to form neurospheres in vitro or tumors when xenotransplanted into the brains of immunocompromised mice.

Conclusions/Significance

These findings support a central role of c-Myc in regulating proliferation and survival of glioma cancer stem cells. Targeting core stem cell pathways may offer improved therapeutic approaches for advanced cancers.

The full text is openly accessible.