angiogenin and Neoplasm-Metastasis

Angiogenesis is essential for tumor growth and metastasis. Many signaling pathways are involved in regulating tumor angiogenesis, with the vascular endothelial growth factor pathway being of particular interest. The recognition of the heterogeneity in tumor vasculature has led to better predictions of prognosis through differential analyses of the vasculature. However, the clinical benefits from antiangiogenic therapy are limited, because many antiangiogenic agents cannot provide long-term survival benefits, suggesting the development of drug resistance. Activation of the hypoxia and c-Met pathways, as well as other proangiogenic factors, has been shown to be responsible for such resistance. Vessel co-option could be another important mechanism. For future development, research to improve the efficacy of antiangiogenic therapy includes (a) using tumor-derived endothelial cells for drug screening; (b) developing the drugs focusing on specific tumor types; (c) developing a better preclinical model for drug study; (d) developing more accurate biomarkers for patient selection; (e) targeting the c-Met pathway or other pathways; and (f) optimizing the dose and schedule of antiangiogenic therapy. In summary, the future of antiangiogenic therapy for cancer patients depends on our efforts to develop the right drugs, select the right patients, and optimize the treatment conditions.

Topics: Angiogenesis Inhibitors; Cell Proliferation; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Microvessels; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Proto-Oncogene Proteins c-met; Ribonuclease, Pancreatic; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factors

Metastatic, rather than primary tumours are responsible for ninety percent cancer deaths. Despite significant advances in the understanding of molecular and cellular mechanisms in tumour metastases, there are limitations in preventive treatment of metastatic tumours. Much evidence arising from laboratory and clinical studies suggests that growth factors and their receptors are implicated in cancer metastases development. We review the origin and production of growth factors and their receptors in all stages of cancer metastases including epithelial-mesenchymal transition, cancer cell invasion and migration, survival within the circulation, seeding at distant organs and metastatic tumour angiogenesis. The functions of growth factors and their receptors are also discussed. This review presents the efforts made in understanding this challenge to aid in the development of new treatment strategies for cancer metastases.

Topics: Angiopoietins; Animals; Apoptosis; Cell Movement; Epidermal Growth Factor; Epithelial-Mesenchymal Transition; ErbB Receptors; Glucose-6-Phosphate Isomerase; Hepatocyte Growth Factor; Humans; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Interleukin-8; Multienzyme Complexes; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Seeding; Neoplasms; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Phosphodiesterase I; Phosphoric Diester Hydrolases; Pyrophosphatases; Receptor, IGF Type 1; Receptors, Growth Factor; Ribonuclease, Pancreatic; Smad Proteins; Snail Family Transcription Factors; Transcription Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Advances in our comprehension of cancer biology and metastasis formation have led to the development of new therapeutic approaches that target tumor biology. The survival and establishment of metastatic lesions depend on a shift in the normal balance of key regulatory factors in favor of angiogenesis. Although a number of these factors have been identified, the most potent regulator of angiogenesis is vascular endothelial growth factor (VEGF). In phase I trials, targeting VEGF with single-agent therapy did not produce clinical benefit for patients, despite promise in preclinical trials. However, the recent data showing that anti-VEGF therapy can enhance the effects of chemotherapy demonstrate the utility in targeting angiogenic factors as a component of antineoplastic regimens. A better understanding of the functions of VEGF allows the development of new hypotheses with regard to its mechanism of action. This article will highlight what is known about colorectal cancer angiogenesis, and will discuss how therapy targeting VEGF may enhance the effects of chemotherapy (and radiation therapy).

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Angiopoietins; Animals; Colorectal Neoplasms; Humans; Integrins; Neoplasm Metastasis; Neovascularization, Pathologic; Platelet-Derived Growth Factor; Receptor, TIE-2; Receptors, Vascular Endothelial Growth Factor; Ribonuclease, Pancreatic; Thrombospondins; Thymidine Phosphorylase; Vascular Endothelial Growth Factors

Changes in the levels of serum cytokines and growth factors are associated with response to therapy. We examined cytokine, chemokine, and growth factor levels in serum collected from normal volunteers or metastatic melanoma patients receiving dendritic cell-based immunotherapy.. Using an array for 42 cytokines, chemokines, or growth factors, sera from normal controls and metastatic melanoma patients at baseline and week 4 were analyzed for qualitative changes. Quantitative determination of the levels of the chemokine thymus and activation-regulated chemokine (TARC/CCL17) was determined by enzyme-linked immunosorbent assay (ELISA).. Significant qualitative differences were noted in serum cytokine, chemokine, and growth factor levels of metastatic melanoma patients versus the normal controls at baseline. The results also demonstrated a significant decrease in the level of angiogenin (P = 0.026) and a significant increase in TARC/CCLl7 (P = 0.008) from week 0 to week 4 which was associated with improved overall survival (P = 0.059). Higher TARC/CCL17 levels were observed by ELISA at week 4 and a log-rank comparison revealed a significant association between high serum TARC/CCL17 levels at week 4 and progression-free survival (P = 0.005). Receiver-operator characteristic analysis revealed that week 4 serum TARC/CCL17 levels were predictive of progression-free and overall survival, indicating that serum TARC/CCL17 might be of predictive value of response to dendritic cell-based anti-melanoma immunotherapy.

Topics: Adolescent; Adult; Biomarkers; Chemokine CCL17; Dendritic Cells; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunotherapy, Adoptive; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Prospective Studies; Ribonuclease, Pancreatic

Metastasis of colorectal cancer (CRC) is the leading cause of CRC-associated mortality. Angiogenin (ANG), a member of the ribonuclease A superfamily, not only activates endothelial cells to induce tumor angiogenesis, but also targets tumor cells to promote cell survival, proliferation and/or migration. However, its clinical significance and underlying mechanism in CRC metastasis are still largely unknown. Here, we reported that ANG was upregulated in CRC tissues and associated with metastasis in CRC patients. We then revealed that ANG enhanced CRC growth and metastasis in both in vitro and in vivo systems. Intriguingly, we characterized a bunch of tRNA-derived stress-induced small RNAs (tiRNAs), produced through ANG cleavage, that was enriched in both CRC tumor tissues and highly metastatic cells, and functioned in ANG-promoted CRC metastasis. Moreover, higher level of a 5'-tiRNA from mature tRNA-Val (5'-tiRNA-Val) was observed in CRC patients and was correlated with tumor metastasis. Taken together, we propose that a novel ANG-tiRNAs-cell migration and invasion regulatory axis promotes CRC metastasis, which might be of potential target for CRC diagnosis and treatment.

Topics: 5' Untranslated Regions; Animals; Case-Control Studies; Cell Movement; Colonic Neoplasms; Gene Knockout Techniques; Heterografts; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Ribonuclease, Pancreatic; RNA, Transfer; Up-Regulation

Tumor angiogenesis is essential for tumor growth and metastasis and is dependent on key angiogenic factors. Angiogenin (ANG), a 14.2-kDa polypeptide member of the RNase A superfamily, is an angiogenic protein that has been reported to be upregulated and associated with poor prognosis in some human cancers. The mechanisms through which aberrant ANG levels promote specific steps in tumor progression are unknown. Here, we show that ANG expression in human tissues is strongly correlated with an invasive cancer phenotype. We also show that ANG induces cellular survival, proliferation, endothelial tube formation and xenograft angiogenesis and growth. Novel mechanistic investigations revealed that ANG expression stimulated matrix metallopeptidase-2 (MMP2) expression through the phosphorylation of ERK1/2. Targeting ANG in vivo with N65828, a small-molecule inhibitor of the ribonucleolytic activity of human ANG, resulted in the diminution of xenograft tumoral growth through the inhibition of angiogenesis. Our findings support an unrecognized interplay between ANG, ERK1/2 and MMP2 that can impact tumor growth and progression. The targeting of ANG and associated factors could provide a novel strategy to inhibit tumor establishment and growth.

Topics: Animals; Cell Line, Tumor; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Heterografts; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Ribonuclease, Pancreatic

Colorectal cancer (CRC) is one of the three leading causes for cancer mortality. CRC kills over 600,000 people annually worldwide. The most common cause of death from CRC is the metastasis to distant organs. However, biomarkers for CRC metastasis remain ill-defined. We compared primary and metastatic CRC cell lines for their angiogenesis-protein profiles and intracellular signaling profiles to identify novel biomarkers for CRC metastasis. To this end, we used primary and metastatic CRC cell lines as a model system and normal human colon cell line as a control. The angiogenesis profiles two isogenic CRC cell lines, SW480 and SW620, and HT-29 and T84 revealed that VEGF was upregulated in both SW620 and T84 whereas coagulation factor III, IGFBP-3, DPP IV, PDGF AA/AB, endothelin I and CXCL16 were downregulated specifically in metastatic cell lines. Furthermore, we found that TIMP-1, amphiregulin, endostatin, angiogenin were upregulated in SW620 whereas downregulated in T84. Angiogenin was downregulated in T84 and GM-CSF was also downregulated in SW620. To induce CRC cell metastasis, we treated cells with pro-inflammatory cytokine IL-6. Upon IL-6 treatment, epithelial-mesenchymal transition was induced in CRC cells. When DLD-1 and HT-29 cells were treated with IL-6; Akt, STAT3, AMPKα and Bad phosphorylation levels were increased. Interestingly, SW620 showed the same signal activation pattern with IL-6 treatment of HT-29 and DLD-1. Our data suggest that Akt, STAT3, AMPKα and Bad activation can be biomarkers for metastatic colorectal cancer. IL-6 treatment specifically reduced phosphorylation levels of EGFR, HER2 receptor, Insulin R and IGF-1R in receptor tyrosine kinase array study with HT-29. Taken together, we have identified novel biomarkers for metastatic CRC through the angiogenesis-antibody array and intracellular signaling array studies. Present study suggests that those novel biomarkers can be used as CRC prognosis biomarkers, and as potential targets for the metastatic CRC therapy.

Topics: Antibodies; Biomarkers, Tumor; Cell Line, Tumor; Chemokine CXCL16; Chemokines, CXC; Colorectal Neoplasms; Dipeptidyl Peptidase 4; Endothelin-1; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Insulin-Like Growth Factor Binding Protein 3; Interleukin-6; Neoplasm Metastasis; Neovascularization, Pathologic; Octamer Transcription Factor-3; Platelet-Derived Growth Factor; Receptors, Scavenger; Ribonuclease, Pancreatic; Signal Transduction; Up-Regulation; Vascular Endothelial Growth Factor A

Staphylococcal nuclease domain-containing 1 (SND1) is a multifunctional protein that is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC). Stable overexpression of SND1 in Hep3B cells expressing a low level of SND1 augments, whereas stable knockdown of SND1 in QGY-7703 cells expressing a high level of SND1 inhibits establishment of xenografts in nude mice, indicating that SND1 promotes an aggressive tumorigenic phenotype. In this study we analyzed the role of SND1 in regulating tumor angiogenesis, a hallmark of cancer. Conditioned medium from Hep3B-SND1 cells stably overexpressing SND1 augmented, whereas that from QGY-SND1si cells stably overexpressing SND1 siRNA significantly inhibited angiogenesis, as analyzed by a chicken chorioallantoic membrane assay and a human umbilical vein endothelial cell differentiation assay. We unraveled a linear pathway in which SND1-induced activation of NF-κB resulted in induction of miR-221 and subsequent induction of angiogenic factors Angiogenin and CXCL16. Inhibition of either of these components resulted in significant inhibition of SND1-induced angiogenesis, thus highlighting the importance of this molecular cascade in regulating SND1 function. Because SND1 regulates NF-κB and miR-221, two important determinants of HCC controlling the aggressive phenotype, SND1 inhibition might be an effective strategy to counteract this fatal malady.

Topics: Carcinoma, Hepatocellular; Cell Nucleus; Chemokine CXCL16; Chemokines, CXC; Endonucleases; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Liver Neoplasms; MicroRNAs; Neoplasm Metastasis; Neovascularization, Pathologic; NF-kappa B; Nuclear Proteins; Receptors, Scavenger; Ribonuclease, Pancreatic; RNA, Small Interfering

Although the expression of angiogenin (ANG), an angiogenic and tumorigenic factor, is elevated in various types of cancers, its regulation mechanism remains unclear. In the present study, in silico search predicted that miR-409-3p targeted to the 3' untranslated region (3'UTR) of the ANG mRNA. Overexpression of miR-409-3p in fibrosarcoma HT1080 cells resulted in decreased steady-state level of ANG transcript and ANG production which were achieved through direct binding of this miRNA to the ANG 3'UTR. The suppressions of miR-409-3p to rRNA transcription, cell proliferation and vasculogenic mimicry could be partially restored by overexpression of ANG with a mutated binding site of miR-409-3p within the ANG 3'UTR. Ectopic expression of miR-409-3p in transplanted HT1080 cells led to the retardation of tumor growth, vascularization and lung metastasis in mouse tumor xenografts. In these xenografts tissues, the expression of miR-409-3p displayed an inverse correlation with ANG, which was also detected in human fibrosarcoma samples. In addition, the suppression effects of miR-409-3p on cell proliferation and angiogenesis in vitro were also found in human umbilical vein endothelial cells. Taken together, these data demonstrate that miR-409-3p inhibits tumor growth, vascularization and metastasis through down-regulating ANG expression.

Topics: 3' Untranslated Regions; Base Sequence; Cell Line, Tumor; Cell Proliferation; DNA Primers; Humans; Immunohistochemistry; MicroRNAs; Neoplasm Metastasis; Neovascularization, Pathologic; Real-Time Polymerase Chain Reaction; Ribonuclease, Pancreatic; RNA, Ribosomal; Transcription, Genetic

Melanoma is a very aggressive and highly angiogenic tumor in which standard treatments have had only limited success. Patients with advanced disease have a 5-year survival rate of 5%. In search for alternatives, we identified a natural product extracted from the fungus Aspergillus niger, termed ACTIBIND, that inhibits tumor growth and metastasis of melanoma in vivo. ACTIBIND, a T2 RNase, exerts antitumorigenic and antiangiogenic activities by competing with the angiogenic factor angiogenin (itself an RNase homologue). Thus, there was decreased expression and activity of the matrix metalloproteinase 2 in melanoma and vascular endothelial cells, decreased vascularization, and increased tumor cell apoptosis in vivo. ACTIBIND significantly inhibited angiogenesis in an in vivo angiogenesis assay with sponges containing angiogenin. In vitro, ACTIBIND was internalized by both melanoma and human umbilical vein endothelial cells, reached the cell nuclei, and inhibited the activity of angiogenin response elements in a dose-dependent manner. Collectively, our data indicate that ACTIBIND should be tested for its potential as a new antiangiogenic modality for the treatment of melanoma.

Topics: Animals; Apoptosis; Aspergillus niger; Cell Growth Processes; Cell Line, Tumor; Drug Interactions; Endoribonucleases; Endothelial Cells; Humans; Luciferases; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; Ribonuclease, Pancreatic; Transcription, Genetic

This work was conducted to find out new potential serum markers and study their role as predictive factors in patients with metastatic melanoma. Serum samples from 68 patients with stage IV malignant melanoma were collected just before current treatment and screened for 79 different cytokines by using a multi-cytokine array. Angiogenin, which is a protein capable of promoting angiogenesis, was found to be markedly elevated among a sub-group of patients with progressive disease (PD) and thus was subjected to further analysis. The mean serum angiogenin level was 270 ng/ml and the median 236 ng/ml (STD 163 ng/ml). Concentrations were significantly higher among men than in women (P = 0.031), whereas patient's age, site of the primary tumour, Clark's or Breslow's classifications were not associated with angiogenin levels. Patients with only lymph node metastases had markedly lower angiogenin levels than those with metastases at other sites (P = 0.05). High angiogenin levels were significantly (P = 0.015; Kruskal-Wallis) associated with poor treatment response with chemoimmunotherapy. Treatment-related survival (TRS) was shorter (10 months) in patients with above-median values than in those with below-median levels (19 months, P = NS). Cox multivariate regression model was used to control for the confounding by the classical prognostic factors of melanoma (age, sex, disease burden, performance score, site of metastases). Disease burden was the only variable that remained in the model as a significant independent predictor of TRS (P = 0.044). These data suggest that serum angiogenin levels might be of predictive value in the evaluation of treatment response for patients with stage IV melanoma.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Ribonuclease, Pancreatic; Skin Neoplasms; Survival Analysis; Treatment Outcome; Tumor Burden

Angiogenin is a potent positive mediator of neovascularization, a process required for both primary tumor growth and metastasis. In the present study, the effect of a fully phosphorothioated antisense oligodeoxynucleotide, designated JF2S, targeting the AUG translation initiation codon region of human angiogenin, on human prostate tumor development and metastasis in athymic mice was examined.. JF2S was evaluated for its capacity to affect in vitro synthesis of angiogenin and subsequent tumorigenicity of transiently transfected prostate tumor cells in mice. In vivo treatment experiments were then conducted in which JF2S was used to prevent formation of tumors in an ectopic model and metastasis in an orthotopic model.. Transient transfection of tumor cells with JF2S inhibited both angiogenin gene expression in vitro and tumorigenicity of these transfected cells in athymic mice. In therapy experiments, local treatment with JF2S completely protected mice from developing prostate tumors after s.c. injection of PC-3 human prostate tumor cells (P < 0.0001, survivor analysis). Most importantly, systemic prophylactic administration of JF2S prevented, in 47% of mice, formation of regional iliac lymph node micrometastases arising from primary tumors growing in the more natural orthotopic prostate setting (P = 0.0003, Fisher's exact test). Furthermore, total protection from regional metastasis occurred in those mice in which JF2S treatment successfully diminished human angiogenin expression in vivo. Tumor-associated angiogenesis was also impaired by JF2S treatment. When therapy was delayed until all of the mice harbored primary tumors in the prostate, the incidence of regional metastasis was still significantly decreased (P < 0.005, survivor analysis).. These findings demonstrate that human prostate cancer establishment and spread in athymic mice is extremely susceptible to targeted disruption of tumor-derived human angiogenin gene expression. Therefore, angiogenin is a valid target against which to devise preventative strategies for prostate cancer metastasis.

Topics: Animals; Blood Vessels; DNA, Antisense; Humans; Male; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Prostatic Neoplasms; Ribonuclease, Pancreatic; RNA, Messenger; Time Factors; Transfection; Tumor Cells, Cultured; Xenograft Model Antitumor Assays