Decitabine may target ovarian CSCs?

Two-Drug Phase I Trial Shows Promise in Treating Late-Stage Ovarian Cancer, ScienceDaily, June 13, 2010. Excerpt:

"Our hypothesis is that decitabine isn't just targeting active ovarian cancer cells, but also cancer stem cells that seem to survive the first treatments," [Kenneth] Nephew said. "By keeping tumor suppression genes from being methylated, carboplatin and other platinum-based treatments for ovarian cancer have a better chance of success in the late stages."

This news release is about the publication entitled: A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer by Fang Fang, Curt Balch and 9 co-authors, including Kenneth P Nephew and Daniela E Matei, Cancer 2010(Jun 8) [Epub ahead of print].

Ovarian CSCs play a role in tumor neovascularization?

Stem-like Ovarian Cancer Cells can Serve as Tumor Vascular Progenitors by Ayesha B Alvero and 8 co-authors, including Gil Mor, Stem Cells 2009(Aug 5) [Epub ahead of print]. PubMed Abstract:

Neovascularization is required for solid tumor maintenance, progression, and metastasis. The most described contribution of cancer cells in tumor neovascularization is the secretion of factors, which attract various cell types to establish a microenvironment that promote blood vessel formation. The cancer stem cell hypothesis suggests that tumors are composed of cells that may share the differentiation capacity of normal stem cells. Similar to normal stem cells, cancer stem cells (CSCs) have the capacity to acquire different phenotypes. Thus, it is possible that CSCs have a bigger role in the process of tumor neovascularization. In this study, we show the capacity of a specific population of ovarian cancer cells with stem-like properties to give rise to xenograft tumors containing blood vessels, which are lined by human CD34+ cells. In addition, when cultured in high-density Matrigel, these cells mimic the behavior of normal endothelial cells and can form vessel-like structures in 24h. Microscopic analysis showed extensive branching and maturation of vessel-like structures in 7 days. Western blot and flow cytometry analysis showed that this process is accompanied by the acquisition of classical endothelial markers, CD34 and VE-cadherin. More importantly, we show that this process is VEGF-independent, but IKKbeta-dependent. Our findings suggest that anti-angiogenic therapies should take into consideration the inherent capacity of these cells to serve as vascular progenitors.

Autophagy and tumor dormancy in human ovarian cancer cells

The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells by Zhen Lu and 11 co-authors, including Robert C. Bast, Jr., J Clin Invest 2008(Dec 1); 118(12): 3917-29. [PubMed Citation]. The last sentence of the Abstract:

Thus, ARHI can induce autophagic cell death, but can also promote tumor dormancy in the presence of factors that promote survival in the cancer microenvironment.

A Commentary: Autophagy-induced tumor dormancy in ovarian cancer by Ravi K Amaravadi, J Clin Invest 2008(Dec 1); 118(12): 3837-40. PubMed Abstract:

Autophagy--a process of "self-eating" that involves enzymatic digestion and recycling of cellular constituents in response to stress--contributes to both cancer cell death and survival. In this issue of the JCI, Lu et al. report that controlled induction of tumor suppressor gene aplasia Ras homolog member I (ARHI) results in autophagic cell death of human ovarian cancer cells in vitro (see the related article beginning on page 3917). However, within xenograft tumors in mice, multiple factors within the tumor microenvironment switched ARHI-induced autophagy to a mechanism of tumor cell survival, leading to tumor dormancy. Since ARHI expression is suppressed in the majority of breast and ovarian cancers but is high in premalignant lesions, ARHI-induced autophagy could be manipulated for therapeutic benefit.

[The JCI publishes all research articles immediately in PubMed Central].

See also: Dormant Cancer Cells Rely on Cellular Self-Cannibalization to Survive, News Release, The University of Texas M. D. Anderson Cancer Center, December 31, 2008.