Angiogenic factors as potential drug target: Efficacy and limitations of anti-angiogenic therapy

Formation of new blood vessels (angiogenesis) has been demonstrated to be a basic prerequisite for sustainable growth and proliferation of tumor. Several growth factors, cytokines, small peptides and enzymes support tumor growth either independently or in synergy. Decoding the crucial mechanisms of angiogenesis in physiological and pathological state has remained a subject of intense interest during the past three decades. Currently, the most widely preferred approach for arresting tumor angiogenesis is the blockade of vascular endothelial growth factor (VEGF) pathway; however, the clinical usage of this modality is still limited by several factors such as adverse effects, toxicity, acquired drug resistance, and non-availability of valid biomarkers. Nevertheless, angiogenesis, being a normal physiological process imposes limitations in maneuvering it as therapeutic target for tumor angiogenesis. The present review offers an updated relevant literature describing the role of well-characterized angiogenic factors, such as VEGF, basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), placenta growth factor (PLGF), hepatocyte growth factor/scatter factor (HGF/SF) and angiopoetins (ANGs) in regulating tumor angiogenesis. We have also attempted to discuss tumor angiogenesis with a perspective of ‘an attractive target with emerging challenges’, along with the limitations and present status of anti-angiogenic therapy in the current state-of-the-art.     

Biomarkers predicting tumor response and evasion to anti-angiogenic therapy

No fully validated biological markers currently exist to predict responsiveness to or the development of evasion to anti-angiogenic therapy of cancer. The identification of such biomarkers is vital to move these therapies forward, as failure to respond to these treatments is often associated with rapid tumor progression that could have been averted had the intrinsic or acquired evasion to anti-angiogenic therapy been identified in a timely fashion. Furthermore, the high cost of antiangiogenic therapies makes it important to avoid utilizing them in the setting of lack of response or developing evasion, making the identification of biomarkers even more important. A number of potential physiologic, circulating, tissue, and imaging biomarkers have emerged from recently completed preclinical animal studies and clinical trials. In this review, we define 5 different types of biomarkers (physiologic, circulating, intratumoral, genetic polymorphisms, and radiographic); discuss the challenges in establishing biomarkers of antiangiogenic therapy in animal models and in clinical trials; and discuss future strategies to identify and validate biomarkers of anti-angiogenic therapy.     

Coevolution in Hybrid Genomes: Nuclear-Encoded Rubisco Small Subunits and Their Plastid-Targeting Translocons Accompanying Sequential Allopolyploidy Events in Triticum

The Triticum/Aegilops complex includes hybrid species resulting from homoploid hybrid speciation and allopolyploid speciation. Sequential allotetra- and allohexaploidy events presumably result in two challenges for the hybrids, which involve 1) cytonuclear stoichiometric disruptions caused by combining two diverged nuclear genomes with the maternal inheritance of the cytoplasmic organellar donor; and 2) incompatibility of chimeric protein complexes with diverged subunits from nuclear and cytoplasmic genomes. Here, we describe coevolution of nuclear rbcS genes encoding the small subunits of Rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase) and nuclear genes encoding plastid translocons, which mediate recognition and translocation of nuclear-encoded proteins into plastids, in allopolyploid wheat species. We demonstrate that intergenomic paternal-to-maternal gene conversion specifically occurred in the genic region of the homoeologous rbcS3 gene from the D-genome progenitor of wheat (abbreviated as rbcS3D) such that it encodes a maternal-like or B-subgenome-like SSU3D transit peptide in allohexaploid wheat but not in allotetraploid wheat. Divergent and limited interaction between SSU3D and the D-subgenomic TOC90D translocon subunit is implicated to underpin SSU3D targeting into the chloroplast of hexaploid wheat. This implicates early selection favoring individuals harboring optimal maternal-like organellar SSU3D targeting in hexaploid wheat. These data represent a novel dimension of cytonuclear evolution mediated by organellar targeting and transportation of nuclear proteins.