Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells
TL;DR: Compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1α may be most effective when IL-8 is simultaneously targeted.
Abstract: Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis. It represents an attractive therapeutic target in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis. In HIF-1alpha knockdown DLD-1 colon cancer cells (DLD-1(HIF-kd)), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1alpha (DLD-1(HIF-wt)). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1(HIF-kd) but not DLD-1(HIF-wt) cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-kappaB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1(HIF-kd) but not DLD-1(HIF-wt) xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1alpha may be most effective when IL-8 is simultaneously targeted.
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TL;DR: The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
9,282 citations
Cites background from "Induction of interleukin-8 preserve..."
...There is also accumulating evidence of interconnections and compensatory pathways between the NF-κB and HIF1α system...
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Journal Article•
2,777 citations
TL;DR: Emerging data support a proposition that two modes of unconventional resistance underlieAngiogenesis inhibitors targeting the vascular endothelial growth factor signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers.
Abstract: In both preclinical and clinical settings, the benefits of angiogenesis inhibitors targeting the vascular endothelial growth factor signalling pathways are at best transitory and followed by restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results.
2,670 citations
09 Mar 2017
TL;DR: An overview of the biology of RCC, with a focus on ccRCC, as well as updates to complement the current clinical guidelines and an outline of potential future directions for RCC research and therapy are provided.
Abstract: Renal cell carcinoma (RCC) denotes cancer originated from the renal epithelium and accounts for >90% of cancers in the kidney. The disease encompasses >10 histological and molecular subtypes, of which clear cell RCC (ccRCC) is most common and accounts for most cancer-related deaths. Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetic regulatory genes and demonstrated marked intra-tumour heterogeneity, which could have prognostic, predictive and therapeutic relevance. Localized RCC can be successfully managed with surgery, whereas metastatic RCC is refractory to conventional chemotherapy. However, over the past decade, marked advances in the treatment of metastatic RCC have been made, with targeted agents including sorafenib, sunitinib, bevacizumab, pazopanib and axitinib, which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR), and everolimus and temsirolimus, which inhibit mechanistic target of rapamycin complex 1 (mTORC1), being approved. Since 2015, agents with additional targets aside from VEGFR have been approved, such as cabozantinib and lenvatinib; immunotherapies, such as nivolumab, have also been added to the armamentarium for metastatic RCC. Here, we provide an overview of the biology of RCC, with a focus on ccRCC, as well as updates to complement the current clinical guidelines and an outline of potential future directions for RCC research and therapy.
1,451 citations
TL;DR: This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.
Abstract: Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells' dependency on these conditions. We engineered three-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. We assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with standard 3D Matrigel culture and in vivo experiments. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.
809 citations
Cites background from "Induction of interleukin-8 preserve..."
...VEGF is commonly considered the main mediator of tumor angiogenesis; however, experimental evidence indicates that its molecular interplay with other proangiogenic factors (for example, IL-8) is critical to this rol...
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TL;DR: The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
Abstract: background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. methods Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. results The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progressionfree survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. conclusions The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
10,161 citations
"Induction of interleukin-8 preserve..." refers background in this paper
...in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therap...
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TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.
Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.
6,024 citations
TL;DR: It is shown that micromolar concentrations of H2O2 can induce the expression and replication of HIV‐1 in a human T cell line and suggests that diverse agents thought to activate NF‐kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI.
Abstract: Hydrogen peroxide and oxygen radicals are agents commonly produced during inflammatory processes. In this study, we show that micromolar concentrations of H2O2 can induce the expression and replication of HIV-1 in a human T cell line. The effect is mediated by the NF-kappa B transcription factor which is potently and rapidly activated by an H2O2 treatment of cells from its inactive cytoplasmic form. N-acetyl-L-cysteine (NAC), a well characterized antioxidant which counteracts the effects of reactive oxygen intermediates (ROI) in living cells, prevented the activation of NF-kappa B by H2O2. NAC and other thiol compounds also blocked the activation of NF-kappa B by cycloheximide, double-stranded RNA, calcium ionophore, TNF-alpha, active phorbol ester, interleukin-1, lipopolysaccharide and lectin. This suggests that diverse agents thought to activate NF-kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI. ROI appear to serve as messengers mediating directly or indirectly the release of the inhibitory subunit I kappa B from NF-kappa B.
3,793 citations
TL;DR: It is shown that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (Hif-1α+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1 α genes (HIF- 1α−/−), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients.
Abstract: As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.
2,391 citations
TL;DR: The role of HIF in developmental, adaptive and neoplastic angiogenesis, and the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype are discussed.
Abstract: The regulation of angiogenesis by hypoxia is an important component of homeostatic mechanisms that link vascular oxygen supply to metabolic demand. Molecular characterization of angiogenic pathways, identification of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydoxylases as a family of dioxygenases that regulate HIF in accordance with oxygen availability have provided new insights into this process. Here we review these findings, and the role of HIF in developmental, adaptive and neoplastic angiogenesis. We also discuss the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype.
2,328 citations