br Concluding Remarks Despite major advances in the developm

Concluding Remarks Despite major advances in the development of antibody and small-molecule tumor angiogenesis inhibitors, therapy resistance, both innate and acquired, continues to limit further survival improvements for patients with cancer. Preclinical models of localized primary tumors and metastatic cancers suggest that HIF-α targeting significantly augments antitumoral and AA effects. More importantly, HIF-α inhibition can synergize with VEGF blockade- or RTKI-based therapies, resulting in decreased tumor burden and favorable survival outcomes. Additionally, the mode of administration of these regimens influences therapeutic efficacy; indeed, the use of LDM therapy within the setting of improved delivery methods, such as nanomedicine, greatly increases the clinical effect of HIF-α blockade and AA agents. Taken together, these data suggest a model in which induction of HIF-α-dependent pathways within the tumor microenvironment can either perpetuate or alleviate IH by modulating tumor vessel density and function. Indeed, anti-VEGF therapy can increase hypoxia by establishing a 94 8 loop promoting HIF-α stabilization and transactivation amplifying HIF-α→VEGF-A signaling (among other downstream targets), leading to resistance and progression [84–88]. This effect does not appear to be limited to CCs, since ECs become resistant to radiotherapy-induced cell death through HIF-α induction and paracrine stimulation by hypoxic CC-derived VEGF-A and bFGF (reviewed in [6]). We suggest that simultaneous targeting of HIF-α and angiogenic pathways would improve clinical responses within the hypoxic tumor microenvironment (Figure 2, Key Figure). Therefore, stratification of patients according to the degree of HIF-α signaling and IH is a crucial requirement to individualize HIF-α/AA combined therapies. The recent development of improved delivery methods for these agents, in conjunction with paralog-specific HIF-1α or HIF-2α inhibitors opens new opportunities to overcome the challenge of AA therapy resistance in human cancers (see Outstanding Questions), whenever associated with hypoxic HIF-α signaling. Importantly, pioneering studies suggest that modulation of HIF-α signaling in the non-malignant tumor stroma is a salient aspect that can influence AA therapy responses through metabolic and immune reprogramming.
Introduction Lophira procera is a plant of family ochnaceaes. its vernacular name (Fang) is Akoga and its trade names are Azobe and Bongossi. It is a giant tree of the damp forest, one of the largest in the African virgin forest, easily recognizable by its slender barrel, fairly light brown and its large oblong, erect leaves and tufts at the ends of the branches at the top. This tree is very widespread in Gabon [1] (Fig. 1). In traditional Gabonese medicine, this plant is used in the treatment of several pathologies. The decoction of barks from this plant is used in lotions against the evil of the kidneys; by an anal route against rheumatism and lumbago, this decoction is also used against chronic gonorrhea, sterility, sexual asthenia, ulcers, rheumatoid arthritis and breast cancers. traditional therapists and phytotherapists define cancer as an accumulation of hard clods in the body and plants that reduce these clods are considered anticancer. Cancers are among the leading causes of morbidity and mortality in the world. In 2012, there were approximately 14 million new cases and 8.2 million deaths related to the disease. The number of new cases is expected to increase by about 70% over the next two decades [2]. Cancer, or malignant tumor, is characterized by a rapid proliferation of abnormal cells which, beyond their usual delimitation, can invade adjacent parts of the organism and then swarm into other organs. It was recognized in 1941 that cancers develop from “subliminal neoplastic states” caused by viral or chemical carcinogenic agents that induce somatic changes [3,4]. Today, these states correspond to “initiation”, involve DNA alterations, are irreversible and can persist in a tissue until a second type of stimulation called “promotion” occurs [5]. Several promoters directly or indirectly induce cell proliferation, recruit inflammatory cells, increase the production of reactive oxygen species (ROS) leading to oxidative damage to DNA and reduce DNA repair, resulting in replication of DNA and proliferation of cells that have lost normal growth control [6]. Studies have shown that ROS are activators of pro-angiogenic substances such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP), the goal of which is to induce angiogenesis [6,7].