Angiogenesis inhibitors increase tumor stem cells

Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Cancer biology & therapy (Impact Factor: 3.07). 06/2012; 13(8):586-7. DOI: 10.4161/cbt.19852
Source: PubMed


The clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway has recently been met with numerous phase III failures that showed modest survival benefits. Understanding the resistance mechanisms of antiangiogenic therapy is essential to overcoming the limited effectiveness of VEGF-pathway inhibitors. A recent study published in the Proceedings of the National Academy of Sciences provides a novel explanation to the treatment limitations of angiogenesis inhibitors and suggests a potential strategy to improve the clinical utility of these agents.

Full-text preview

Available from:
  • Source
    • "07/23/14 3:22pm Page 1 counteracting the buildup of therapeutic intracellular concentrations . Since many organ systems require a high expression of such transport proteins in order to maintain physiological integrity, the administration of classical or tailored AU4 c MDR-modulators to overcome multidrug resistance often results in therapy failure due to fatal systemic toxicity (Tannock, 2001; Donnenberg and Donnenberg, 2005; Lu and Shervington, 2008; Nakai et al., 2009; Sabisz and Skladanowski, 2009; Baguley, 2010; Gillet and Gottesman, 2010; Bao et al., 2012, 2014; Chau and Figg, 2012; Cheng et al., 2012; De Palma and Nucera, 2012; Hu et al., 2012; Cao et al., 2013; Chekhonin et al., 2013; Prigione et al., 2014). Current cancer therapies may also be rendered inefficient by the selection or induction of cancer stem cells (CSCs) and the associated cellular heterogeneity (Hansen et al., 1997; Erenpreisa et al., 2008; Bartkowiak et al., 2009; McCord et al., 2009; Díaz-Carballo et al., 2010; Mo and Zhang, 2012; Mascre et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Until recently, acquired resistance to cytostatics had mostly been attributed to biochemical mechanisms such as decreased intake and/or increased efflux of therapeutics, enhanced DNA repair, and altered activity or deregulation of target proteins. Although these mechanisms have been widely investigated, little is known about membrane barriers responsible for the chemical imperviousness of cell compartments and cellular segregation in cytostatic-treated tumors. In highly heterogeneous cross-resistant and radiorefractory cell populations selected by exposure to anticancer agents, we found a number of atypical recurrent cell types in (1) tumor cell cultures of different embryonic origins, (2) mouse xenografts, and (3) paraffin sections from patient tumors. Alongside morphologic peculiarities, these populations presented cancer stem cell markers, aberrant signaling pathways, and a set of deregulated miRNAs known to confer both stem-cell phenotypes and highly aggressive tumor behavior. The first type, named spiral cells, is marked by a spiral arrangement of nuclei. The second type, monastery cells, is characterized by prominent walls inside which daughter cells can be seen maturing amid a rich mitochondrial environment. The third type, called pregnant cells, is a giant cell with a syncytium-like morphology, a main nucleus, and many endoreplicative functional progeny cells. A rare fourth cell type identified in leukemia was christened shepherd cells, as it was always associated with clusters of smaller cells. Furthermore, a portion of resistant tumor cells displayed nuclear encapsulation via mitochondrial aggregation in the nuclear perimeter in response to cytostatic insults, probably conferring imperviousness to drugs and long periods of dormancy until nuclear eclosion takes place. This phenomenon was correlated with an increase in both intracellular and intercellular mitochondrial traffic as well as with the uptake of free extracellular mitochondria. All these cellular disorders could, in fact, be found in untreated tumor cells but were more pronounced in resistant entities, suggesting a natural mechanism of cell survival triggered by chemical injury, or a primitive strategy to ensure stemming, self-renewal, and differentiation under adverse conditions, a fact that may play a significant role in chemotherapy outcomes. ahead of print. doi:10.1089/dna.2014.2375. Online Ahead of Print: August 15, 2014 accepted June 29, 2014 received in revised form June 28, 2014 received for publication February 3, 2014
    Full-text · Article · Aug 2014 · DNA and Cell Biology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenesis is defined as the formation and the growth of new blood vessels that sprout from existing vascular network. Angiogenesis plays a very important role in the physiological and pathological situations such as ischemia, atherosclerosis, wound healing, and cancer growth and metastasis. Microarray is a new molecular biological technique that can analyze expression of hundreds to thousands of genes or proteins simultaneously in a single experiment. Microarray includes DNA microarray, protein microarray, tissue microarray, and cell microarray. Many different types of microarray chips are now commercially available, some designed specifically for angiogenesis. MicroRNAs (miRNAs) are endogenous, short, noncoding RNAs found in eukaryotic cells. MiRNAs are posttranscriptional regulators that negatively regulate gene expression by binding to their target messenger RNAs for degradation and/or translational repression. The main function of miRNAs is gene regulation. MiRNAs have been found to modulate many pathophysiological process including cell differentiation, contraction, migration, proliferation, apoptosis, and tissue inflammation. There are more than 1,000 miRNAs in human genome, some of them are involved in angiogenesis. In this review, we will summarize the application of microarray assay and function of miRNAs in angiogenesis.
    No preview · Chapter · Jan 2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: Robust neovascularization and lymphangiogenesis have been found in a variety of aggressive and metastatic tumors. Endothelial sprouting angiogenesis is generally considered to be the major mechanism by which new vasculature forms in tumors. However, increasing evidence shows that tumor vasculature is not solely comprised of endothelial cells (ECs). Some tumor cells acquire processes similar to embryonic vasculogenesis and produce new vasculature through vasculogenic mimicry, trans-differentiation of tumor cells into tumor ECs, and tumor cell-EC vascular co-option. In addition, tumor cells secrete various vasculogenic factors that induce sprouting angiogenesis and lymphangiogenesis. Vasculogenic tumor cells actively participate in the formation of vascular cancer stem cell niche and a premetastatic niche. Therefore, tumor cell-mediated neovascularization and lymphangiogenesis are closely associated with tumor progression, cancer metastasis, and poor prognosis. Vasculogenic tumor cells have emerged as key players in tumor neovascularization and lymphangiogenesis and play pivotal roles in tumor progression and cancer metastasis. However, the mechanisms underlying tumor cell-mediated vascularity as they relate to tumor progression and cancer metastasis remain unclear. Increasing data have shown that various intrinsic and extrinsic factors activate oncogenes and vasculogenic genes, enhance vasculogenic signaling pathways, and trigger tumor neovascularization and lymphangiogenesis. Collectively, tumor cells are the instigators of neovascularization. Therefore, targeting vasculogenic tumor cells, genes, and signaling pathways will open new avenues for anti-tumor vasculogenic and metastatic drug discovery. Dual targeting of endothelial sprouting angiogenesis and tumor cell-mediated neovascularization and lymphangiogenesis may overcome current clinical problems with anti-angiogenic therapy, resulting in significantly improved anti-angiogenesis and anti-cancer therapies.
    No preview · Article · Aug 2013 · Biochimica et Biophysica Acta