Antiangiogenesis therapy in the treatment of metastatic colorectal cancer.
ABSTRACT: The process of new blood vessel formation, or angiogenesis, has become an important target for therapeutic intervention in many cancers, including metastatic colorectal cancer (mCRC). The growth and metastasis of primary tumors is dependent upon their ability to acquire and maintain an adequate blood supply; however, angiogenesis in tumors is an irregular process leading to chaotic and hyperpermeable vessels that may result in increased intratumoral pressure and poor exchange of macromolecules and oxygen. It has been hypothesized that inhibition of angiogenesis in tumors can both impair the formation of new tumor blood vessels and possibly 'normalize' the existing tumor vasculature, causing a more efficient delivery of cytotoxic chemotherapies (CTs). Over the last decade, therapies that target vascular endothelial growth factor (VEGF) have become a component of treatment for several cancers. In particular, the combination of bevacizumab with established chemotherapeutic regimens for mCRC has been shown to improve overall and progression-free survival, as well as response rates, over CT alone. Agents that target various members of the VEGF family, as well as signaling by the VEGF receptors and their tyrosine kinase components, are currently under development and evaluation in clinical trials. Integration of these new therapies into the treatment of mCRC will ultimately increase the available therapeutic options for patients. Still, many challenges remain, including identifying and validating relevant biomarkers to guide the optimal use of antiangiogenesis agents.
Project description:Drugs that target the tumor vasculature and inhibit angiogenesis are widely used for cancer treatment. Individual tumors show large differences in vascularity, but it is uncertain how these differences affect responsiveness to antiangiogenesis. We investigated this question using two closely related prostate cancer models that differ markedly in tumor vascularity: PC3, which has very low vascularity, and the PC3-derived cancer stem-like cell holoclone PC3/2G7, which forms tumors with high microvessel density, high tumor blood flow, and low hypoxia compared with parental PC3 tumors. Three angiogenesis inhibitors (axitinib, sorafenib, and DC101) all induced significantly greater decreases in tumor blood flow and microvessel density in PC3/2G7 tumors compared with PC3 tumors, as well as significantly greater decreases in tumor cell proliferation and cell viability and a greater increase in apoptosis. The increased sensitivity of PC3/2G7 tumors to antiangiogenesis indicates they are less tolerant of low vascularity and suggests they become addicted to their oxygen- and nutrient-rich environment. PC3/2G7 tumors showed strong upregulation of the proangiogenic factors chemokine ligand 2 (CCL2) and VEGFA compared with PC3 tumors, which may contribute to their increased vascularity, and they have significantly lower endothelial cell pericyte coverage, which may contribute to their greater sensitivity to antiangiogenesis. Interestingly, high levels of VEGF receptor-2 were expressed on PC3 but not PC3/2G7 tumor cells, which may contribute to the growth static response of PC3 tumors to VEGF-targeted antiangiogenesis. Finally, prolonged antiangiogenic treatment led to resumption of PC3/2G7 tumor growth and neovascularization, indicating these cancer stem-like cell-derived tumors can adapt and escape from antiangiogenesis.
Project description:The tumor vasculature delivers nutrients, oxygen, and therapeutic agents to tumor cells. Unfortunately, the delivery of anticancer drugs through tumor blood vessels is often inefficient and can constitute an important barrier for cancer treatment. This barrier can sometimes be circumvented by antiangiogenesis-induced normalization of tumor vasculature. However, such normalizing effects are transient; moreover, they are not always achieved, as shown here, when 9L gliosarcoma xenografts were treated over a range of doses with the VEGF receptor-selective tyrosine kinase inhibitors axitinib and AG-028262. The suppression of tumor blood perfusion by antiangiogenesis agents can be turned to therapeutic advantage, however, through their effects on tumor drug retention. In 9L tumors expressing the cyclophosphamide-activating enzyme P450 2B11, neoadjuvant axitinib treatment combined with intratumoral cyclophosphamide administration significantly increased tumor retention of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide. Similar increases were achieved using other angiogenesis inhibitors, indicating that increased drug retention is a general response to antiangiogenesis. This approach can be extended to include systemic delivery of an anticancer prodrug that is activated intratumorally, where antiangiogenesis-enhanced retention of the therapeutic metabolite counterbalances the decrease in drug uptake from systemic circulation, as exemplified for cyclophosphamide. Importantly, the increase in intratumoral drug retention induced by neoadjuvant antiangiogenic drug treatment is shown to increase tumor cell killing and substantially enhance therapeutic activity in vivo. Thus, antiangiogenic agents can be used to increase tumor drug exposure and improve therapeutic activity following intratumoral drug administration, or following systemic drug administration in the case of a therapeutic agent that is activated intratumorally.
Project description:Timosaponin AIII (Timo AIII) is a natural steroidal saponin isolated from the traditional Chinese herb Anemarrhena asphodeloides Bge with proved effectiveness in the treatment of numerous cancers. However, whether Timo AIII suppresses tumor angiogenesis remains unclear. In the present study, we investigated the antiangiogenesis effects of Timo AIII and the underlying mechanisms in human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish embryos in vivo. We showed that treatment with Timo AIII (0.5-2?µM) partially disrupted the intersegmental vessels (ISVs) and subintestinal vessels (SIVs) growth in transgenic zebrafish Tg(fli-1a: EGFP)y1. Timo AIII (0.5-4?µM) dose-dependently inhibited VEGF-induced proliferation, migration, invasion, and tube formation of HUVECs, but these inhibitory effects were not due to its cytotoxicity. We further demonstrated that Timo AIII treatment significantly suppressed the expression of VEGF receptor (VEGFR) and the phosphorylation of Akt, MEK1/2, and ERK1/2 in HUVECs. Timo AIII treatment also significantly inhibited VEGF-triggered phosphorylation of VEGFR2, Akt, and ERK1/2 in HUVECs. Moreover, we conducted RNA-Seq and analyzed the transcriptome changes in both HUVECs and zebrafish embryos following Timo AIII treatment. The coexpression network analysis results showed that various biological processes and signaling pathways were enriched including angiogenesis, cell motility, cell adhesion, protein serine/threonine kinase activity, transmembrane signaling receptor activity, growth factor activity, etc., which was consistent with the antiangiogenesis effects of Timo AIII in HUVECs and zebrafish embryos. We conclude that the antiangiogenesis effect of Timo AIII is mediated through VEGF/PI3K/Akt/MAPK signaling cascade; Timo AIII potentially exerts antiangiogenesis effect in cancer treatment.
Project description:We describe that galectin-1 (gal-1) is a receptor for the angiogenesis inhibitor anginex, and that the protein is crucial for tumor angiogenesis. gal-1 is overexpressed in endothelial cells of different human tumors. Expression knockdown in cultured endothelial cells inhibits cell proliferation and migration. The importance of gal-1 in angiogenesis is illustrated in the zebrafish model, where expression knockdown results in impaired vascular guidance and growth of dysfunctional vessels. The role of gal-1 in tumor angiogenesis is demonstrated in gal-1-null mice, in which tumor growth is markedly impaired because of insufficient tumor angiogenesis. Furthermore, tumor growth in gal-1-null mice no longer responds to antiangiogenesis treatment by anginex. Thus, gal-1 regulates tumor angiogenesis and is a target for angiostatic cancer therapy.
Project description:Both malignant tumor growth and metastasis are dependent upon angiogenesis, a process of new blood vessel formation. Inhibition of this process by specific inhibitors might be able to control tumor growth and metastasis. Therefore, antiangiogenesis thereapy is considered a promising strategy and being studied worldwide. A wide variety of angiogenesis inhibitors have been identified and some of them are under clinical trials in the advanced patients with cancer including gastric cancer. This review summarizes the development and progress of angiogenesis inhibitors in recent decades, and discusses the future direction of antiangiogenesis research, and the potential antiangiogenic agents which are most likely to be translated into standard treatment for gastrointestinal cancer patients either alone or combined with other therapies.
Project description:Caveolin-1, the signature protein of endothelial cell caveolae, has many important functions in vascular cells. Caveolae are thought to be the transcellular pathway by which plasma proteins cross normal capillary endothelium, but, unexpectedly, cav-1(-/-) mice, which lack caveolae, have increased permeability to plasma albumin. The acute increase in vascular permeability induced by agents such as vascular endothelial growth factor (VEGF)-A occurs through venules, not capillaries, and particularly through the vesiculo-vacuolar organelle (VVO), a unique structure composed of numerous interconnecting vesicles and vacuoles that together span the venular endothelium from lumen to ablumen. Furthermore, the hyperpermeable blood vessels found in pathological angiogenesis, mother vessels, are derived from venules. The present experiments made use of cav-1(-/-) mice to investigate the relationship between caveolae and VVOs and the roles of caveolin-1 in VVO structure in the acute vascular hyperpermeability induced by VEGF-A and in pathological angiogenesis and associated chronic vascular hyperpermeability. We found that VVOs expressed caveolin-1 variably but, in contrast to caveolae, were present in normal numbers and with apparently unaltered structure in cav-1(-/-) mice. Nonetheless, VEGF-A-induced hyperpermeability was strikingly reduced in cav-1(-/-) mice, as was pathological angiogenesis and associated chronic vascular hyperpermeability, whether induced by VEGF-A(164) or by a tumor. Thus, caveolin-1 is not necessary for VVO structure but may have important roles in regulating VVO function in acute vascular hyperpermeability and angiogenesis.
Project description:Radiotherapy is a vitally important strategy for clinical treatment of malignant cancers. Therefore, rational design and development of radiosensitizers that could enhance radiotherapeutic efficacy has attracted tremendous attention. Antiangiogenesis therapy could be a potentially effective strategy to regulate tumor growth and metastasis due to angiogenesis plays a pivotal role for tumor growth, invasion and metastasis to other organs. Herein, we have rationally designed a smart and effective nanosystem by combining ultrasmall selenium nanoparticles and bevacizumab (Avastin™, Av), for simultaneous radiotherapy and antiangiogenic therapy of cancer. The nanosystem was further coated with red blood cell (RBC) membranes to develop the final construct, RBCs@Se/Av. The RBC membrane coating effectively prolongs the blood circulation time and reduces the elimination of the nanosystem by autoimmune responses. As expected, RBCs@Se/Av, when irradiated with X-ray demonstrated potent anticancer and antiangiogenesis response in vitro and in vivo, as evidenced by strong inhibition of A375 tumor growth in nude mice, without causing any obvious histological damage to the non-target major organs. Taken together, this study demonstrates an effective strategy for design of smart Se-based nanosystem decorated with RBC membrane for simultaneous cancer radiosensitization and precise antiangiogenesis.
Project description:Curcumin has diverse biological activities, but is known to undergo rapid metabolism via reduction of vinylic double bonds and phase II conjugation. To prevent reductive metabolism of curcumin, we introduced a methyl group at both C2 and C6 positions (compound 1) or at the C2 position (compound 2) of curcumin, creating steric hindrance on double bonds against metabolizing enzymes. As predicted, these compounds were resistant to reduction by alcohol dehydrogenase. Compound 1 was further evaluated for its antiangiogenesis activity in vitro and in vivo. It exhibited significantly greater inhibitory activity than curcumin against endothelial cell migration, invasion, and tube formation. Similarly, the in vivo Matrigel plug assay in C57BL/6 mice showed more pronounced reduction of blood vessels in the plugs containing 1 than those containing curcumin. Moreover, 1 suppressed tumor growth more effectively than curcumin in a U87MG mouse xenograft model by inhibiting angiogenesis. In vivo metabolite analysis by liquid chromatography/mass spectrometry demonstrated that 1 underwent markedly slower reductive metabolism than curcumin. Taken together, our results indicate that 1 has enhanced antiangiogenesis activity and suppression of tumor growth compared with curcumin, reflecting diminished reductive metabolism owing to the introduction of methyl groups at the C2 and C6 positions of curcumin.
Project description:There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy.A total of 132 patients treated with first-line bevacizumab and FOLFOX or XELOX were included in this study. Genomic DNA was isolated from whole-blood samples by PCR-RFLP or direct DNA sequencing. The endpoints of the study were progression-free survival (PFS), overall survival (OS), and response rate (RR).The minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased OS and remained significant in multivariate Cox regression analysis (HR: 0.52; 95% CI: 0.31-0.87; adjusted P = 0.012 and HR: 0.60; 95% CI: 0.36-0.99; adjusted P = 0.046, respectively). The minor allele of HIF1? rs11549465 C>T was significantly associated with increased PFS but lost its significance in multivariate analysis. CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A, and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (P(act) = 0.003).In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy.
Project description:Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin(+) perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.