Growth Of Human Colon Cancer Research Articles

Retraction Note: SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin

Retraction Note: SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin

Tenglong Buzhong granules inhibits the growth of SW620 human colon cancer.

To observe the anticancer effects of the granular preparation of Tenglong Buzhong decoction (,TBD), i.e Tenglong Buzhong granules (, TBG), in human SW620 colon cancer. BALB/c nude mice were subcutaneously transplanted with SW620 cells, and treated with TBG (2.56 g/kg, once per day) and/or 5-Fu (104 mg/kg, once per week) for 21 d. Apoptosis, Caspase activities and cellular senescence were measured by commercial kits. The protein expression and phosphorylation were detected by Western blot or immunohistochemistry. TBG and 5-Fu inhibited tumor growth. The tumor inhibition rate of the TBG, 5-Fu, and TBG+5-Fu groups was 42.25%, 51.58%, and 76.08%, respectively. Combination of TBG and 5-Fu showed synergetic anti-cancer effects. TBG and 5-Fu induced apoptosis, activated caspase-3, -8, and -9, increased SMAC expression, inhibited XIAP expression. TBG induced cellular senescence, upregulated cyclin-dependent kinase inhibitor 1a (CDKN1a) and cyclin-dependent kinase inhibitor 2a (CDKN2a) expression, and inhibited phosphorylation of retinoblastoma-associated protein (RB) and expression of cyclin E1 (CCNE1) and cyclin-dependent kinases (CDK) 2. TBG also inhibited angiogenesis accompanied by downregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α). TBG inhibits SW620 colon cancer growth, induces apoptosis SMAC-XIAP-Caspases signaling, induces cellular senescence through CDKN1a/CDKN2a-RB-E2F signaling, inhibits angiogenesis by down-regulation of HIF-1α and VEGF, and enhances the effects of 5-Fu.

Ginger polysaccharide UGP1 suppressed human colon cancer growth via p53, Bax/Bcl-2, caspase-3 pathways and immunomodulation

In previous study, we got a purified ginger polysaccharide UGP1 and verified its significant antitumor activities on colon cancer HCT116 cells. In this article, we aimed to illustrate the underlying mechanism of UGP1 exerted antitumor activities on colon cancer by using in vitro cell models and in vivo animal models. The results demonstrated that UGP1 could induce S-phase cell cycle arrest, up-regulate the expression of Bax and p53, down-regulate the expression of Bcl-2, and activate the downstream protein caspase-9 and caspase-3, which was related to intrinsic apoptosis pathway on HCT116 cells. Moreover, UGP1 significantly stimulated RAW264.7 cell proliferation and secretion activity. Similarly, UGP1 inhibited tumor proliferation on tumor-bearing mice, increased the expression of p53 and the ratio of Bax/Bcl-2, enhanced the secretion of pro-inflammatory cytokines TNF-α, IL-2, IL-6 and decreased the secretion of pro-tumor cytokines TGF-β and bFGF in serum. In conclusion, it indicated that the UGP1 could suppress human colon cancer growth by inducing apoptosis via the regulation of p53, caspase-3, and Bax/Bcl-2 ratio-dependent pathway and regulating immune system activity. This investigation provided basic theoretical mechanism of ginger polysaccharide-exerted antitumor activities, and contributed to develop a possible functional food or adjuvant agent for prevention or treatment of colon cancer.

Prolyl 4-hydroxylase subunit alpha 3 facilitates human colon cancer growth and metastasis through the TGF-β/Smad signaling pathway

Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) has been known to be associated with a variety of human cancers. However, the role of P4HA3 on colon cancer growth and metastasis is unclear. In this study, we investigated the effect of P4HA3 on the growth and metastasis of colon cancer and its possible molecular mechanism. First of all, we demonstrated that P4HA3 expression was greatly higher in cells and tissues of colon cancer than that in non-tumor tissues and cells, and the prognosis of patients who had higher P4HA3 was distinctively poorer than patients who had lower level of P4HA3. Second, it was shown that P4HA3 knockdown strongly inhibited the migration, proliferation and invasion ability of colon cancer cells. However, P4HA3 over-expression accelerated the abilities. Meanwhile, P4HA3 could promote subcutaneous tumorigenesis in nude mice in vivo. In addition, P4HA3 knockdown significantly decreased mesenchymal markers Vimentin, N-cadherin and Snail expression and increased epithelial marker E-cadherin expression. And conversely, over-expression of P4HA3 produced the opposite effects. In the current study, there was further evidence that down-regulating P4HA3 significantly reduced both TGF-β and its following molecules including p-Smad2 as well as p-Smad3. However, overexpression of P4HA3 showed the opposite effect. In conclusion, this study shows that P4HA3 promotes the human colon cancer growth and metastasis by affecting TGF-β/Smad signaling pathway. P4HA3 may become a new target for early diagnosis, treatment and prognosis assessment of colon cancer.

Engineering NK-92 Cell by Upregulating CXCR2 and IL-2 Via CRISPR-Cas9 Improves Its Antitumor Effects as Cellular Immunotherapy for Human Colon Cancer.

Natural killer (NK) cells have shown good application prospects in adoptive cellular immunotherapy against cancer. However, due to its insufficient infiltration and low activity, the therapeutic effect of infused NK cells has been limited in solid tumors, such as colorectal cancer. It has been proved that tumor-produced chemokines regulate the migration of NK cells expressing corresponding chemokine receptors, and cytokines could enhance the antitumor activity of NK cells. In this study, we innovatively upregulated the expression of chemokine receptor CXC chemokine receptor 2 (CXCR2) and cytokine interleukin (IL)-2 on NK-92 cells using CRISPR-Cas9 gene-editing technology. We demonstrated that overexpressing CXCR2 and IL-2 promotes NK-92 cells to increasingly transfer into tumor sites and achieve stronger cell-killing and proliferation activity. Moreover, the inhibitory effects of gene-edited NK-92 cells on the growth of human colon cancer in vivo were also improved. The tumor burden of tumor-bearing mice was reduced, and their survival time was significantly prolonged. Gene-editing modification NK cells are expected to become a novel and promising tumor treatment strategy.

A Novel Artificially Humanized Anti-Cripto-1 Antibody Suppressing Cancer Cell Growth.

Cripto-1 is a member of the EGF-CFC/FRL1/Cryptic family and is involved in embryonic development and carcinogenesis. We designed a novel anti-Cripto-1 artificial antibody and assessed the recognition to the antigen and the potential to suppress the growth of cancer stem cells. First, single chain antibody clones were isolated by bio-panning with the affinity to recombinant Cripto-1 protein from our original phage-display library. Then, the variable regions of heavy chain VH and light chain VL in each clone were fused to constant regions of heavy chain CH and light chain CL regions respectively. These fused genes were expressed in ExpiCHO-S cells to produce artificial humanized antibodies against Cripto-1. After evaluation of the expression levels, one clone was selected and the anti-Cripto-1 antibody was produced and purified. The purified antibody showed affinity to recombinant Cripto-1 at 1.1 pmol and immunoreactivity to cancer tissues and cell lines. The antibody was available to detect the immunoreactivity in tissue microarrays of malignant tumors as well as in Cripto-1 overexpressing cells. Simultaneously, the antibody exhibited the potential to suppress the growth of human colon cancer derived GEO cells overexpressing Cripto-1 with IC50 at approximately 110 nM. The artificially humanized antibody is proposed to be a good candidate to target cancer cells overexpressing Cripto-1.

Discovery of a novel dual-target inhibitor against RSK1 and MSK2 to suppress growth of human colon cancer.

Colon cancer is the most aggressive tumor in both men and women globally. As many the chemotherapeutic regimens have adverse side effects and contribute to the resistance and recurrence, therefore, finding novel therapeutic targets and developing effective agents are urgent. Based on the TCGA and GTEx database analysis, RSK1 and MSK2 were found abnormal expressed in colon cancer. RSK1 and MSK2 were overexpressed in colon cancer tissues confirmed by western blot and IHC. After knocking down RSK1 or MSK2, cell proliferation and anchorage-independent cell growth were markedly inhibited. Using a computer docking model, we identified a novel dual-target inhibitor, APIO-EE-07, that could block both RSK1 and MSK2 kinase activity in a dose-dependent manner. APIO-EE-07 inhibited cell growth and induced apoptosis and also increased expression of Bax as well as cleaved caspase-3 and -PARP in colon cancer cells by downregulating RSK1 and MSK2 downstream targets, including CREB and ATF1. Furthermore, APIO-EE-07 decreased tumor volume and weight in human patient-derived xenografts tumors implanted in SCID mice. In summary, our results demonstrate that RSK1 and MSK2 are the potential targets for the treatment of colon cancer. APIO-EE-07, a novel dual-target inhibitor of RSK1 and MSK2, can suppress the growth of colon cancer by attenuating RSK1 and MSK2 signaling.

Ginsenoside Rg3 enhances the anticancer effect of 5‑FU in colon cancer cells via the PI3K/AKT pathway.

Chemotherapy is one of the most commonly used treatments for patients with advanced colon cancer, yet the toxicity of chemotherapy agents, such as 5-fluorouracil (5-FU), limits the effectiveness of chemotherapy. Ginsenoside Rg3 (Rg3) is an active ingredient isolated from ginseng. Rg3 has been shown to display anticancer effects on a variety of malignancies. Yet, whether Rg3 synergizes the effect of 5-FU to inhibit the growth of human colon cancer remains unknown. The present study was designed to ascertain whether Rg3 is able to enhance the anti-colon cancer effect of 5-FU. The results revealed that combined treatment of Rg3 and 5-FU significantly enhanced the inhibition of the proliferation, colony formation, invasion and migration of human colon cancer cells (SW620 and LOVO) in vitro. We also found that combined treatment of Rg3 and 5-FU significantly enhanced the apoptosis of colon cancer cells by activating the Apaf1/caspase 9/caspase 3 pathway and arrested the cell cycle of the colon cancer cells in G0/G1 by promoting the expression of Cyclin D1, CDK2 and CDK4. In addition, the PI3K/AKT signaling pathway in colon cancer cells was suppressed by Rg3 and 5-FU. In vivo, Rg3 synergized the effect of 5-FU to inhibit the growth of human colon cancer xenografts in nude mice. Similarly, combined treatment of Rg3 and 5-FU altered the expression of colon cancer protein in vivo and in vitro. Collectively, the present study demonstrated that ginsenoside Rg3 enhances the anticancer effect of 5-FU in colon cancer cells via the PI3K/AKT pathway.

Synthesis and Anticancer Activity of Novel Actinonin Derivatives as HsPDF Inhibitors.

Human mitochondrial peptide deformylase (HsPDF) is responsible for removing the formyl group from N-terminal formylmethionines of newly synthesized mitochondrial proteins and plays important roles in maintaining mitochondria function. It is overexpressed in various cancers and has been proposed as a novel therapeutic target. Actinonin, a naturally occurring peptidomimetic HsPDF inhibitor, was reported to inhibit the proliferation of a broad spectrum of human cancer cells in vitro. However, its efficacy and pharmacokinetic profile requires significant improvement for therapeutic purposes. To obtain HsPDF inhibitors as anticancer therapeutics, we screened an in-house collection of actinonin derivatives and found two initial hits with antiproliferation activity. Further optimization along the peptidomimetic backbone lead to two series of compounds containing substituted phenyl moieties. They are potent HsPDF inhibitors and exhibited greatly improved antiproliferation activity in selected cancer cell lines. Finally, compound 15m significantly inhibited the growth of human colon cancer in xenograft animal models.

Abstract 203: Pseudosemiglabrin inhibits tumor angiogenesis and tumor growth of human colon cancer in xenograft mouse models by downregulating endothelial functions, Notch and VEGF pathways

Abstract Many antineoplasic agents were identified from natural product. One such agent is (-)-pseudosemiglabrin extracted from aerial parts of Tephrosia apollinea, while significant progress has been made in understanding the antineoplasic and anti-inflammatory of prenylated flavone (-)-pseudosemiglabrin (SSG), little is known about its antiangiogenic and antitumor in vivo. Using rat aortic ring assay and zebrafish model, SSG dramatically suppressed angiogenesis in vitro, ex vivo and in vivo models, SSG profoundly inhibited the outgrowth of new vessels from explants rat aortic ring, moreover it impaired human endothelial cells (HUVEC) migration and formation of capillary-like structure in vitro in none toxic doses. In this study we hypothesize that SSG can hampered tumor angiogenesis and tumor growth of colorectal cancer in ectopically and orthotopically implanted in nude mice, oral administration of SSG (25- 100mg/kg) significantly inhibited colon tumors growth in nude mice. Histological and Immunohistochemistry analysis further revealed that the stained blood vessels and expression of CD31 in xenograft were remarkably decreased in tumors excised from animals treated with SSG. Mechanistically the compound inhibits tumor angiogenesis by downregulation of Notch downstream (NCID); also SSG was found to inhibit VEGF secretion from human cancer cells as well as endothelial cells. In conclusion, the results demonstrated an original role of (-)-pseudosemiglabrin in inhibiting tumor angiogenesis and tumor growth via inhibition Notch and VEGF pathways. This study also validates the central role of Notch in tumor angiogenesis and suggests that (-)-pseudosemiglabrin could be a potential therapeutic candidate for cancer and other angiogenesis related diseases. Note: This abstract was not presented at the meeting. Citation Format: Loiy E. Ahmed Hassan, Azman Seeni, Amin M. Abdul Majid. Pseudosemiglabrin inhibits tumor angiogenesis and tumor growth of human colon cancer in xenograft mouse models by downregulating endothelial functions, Notch and VEGF pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 203.

Colonic Epithelial Cells Express an Oncolytic Bispecific IgA/IgG heterodimer

The gastrointestinal epithelium sheds about 10(12) cells per day. Contrary to conventional wisdom a majority of these cells (>90%) are excreted into the fecal stream intact. We first demonstrated the isolation of these cells in a viable state (1991) and showed the feasibility of studying the expression of various bomarkers in health and disease. During the course of our studies mapping the expression of surface markers using flow cytometry we discovered that these cells had the ability to destroy a variety of cancer cells. These colonic cells expressed among other markers (COX‐2 during an inflammatory condition) IgA and IgG along with a subpopulation of cells co‐expressing IgA/IgG. Blocking the IgG component with anti‐IgG antibody discharged the oncolytic property of these cells. We also observed that these cells expressed Lgr5 and Musashi1, the putative markers of gastrointestinal progenitor stem cells. Long term tissue culture experiments revealed the persistence of the heterodimer. In a cohort of 80 random human samples we observed the absence of this hybrid IgA/IgG antibody in two subjects of African American origin. Lineage directed differentiation of these cells generated a progeny that secreted this chimeric antibody. This antibody was shown to arrest the growth of human colon cancer in xenotransplants in nude mice. From these observations It was concluded that this is a novel native antibody that may be absent in certain individuals as a result of a genetic aberration.Support or Funding InformationSBIR grants R43 & R44 DK‐56567 and R‐43 & R‐44 CA‐81799 from the NIDDK and NCI of the National Institutes of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

In silico, in vitro and in vivo Tests of Ficus deltoidea Jack Leaves Extract as Inhibitor for Beta-Catenin Expression in Colon Carcinogenesis Model

Context: Ficus deltoidea Jack leaves extract as anticolorectal cancer. Aims: This study aims to analyze the potential of FD extract to be an anti-colon cancer by investigating the extract capability in reducing β-catenin expression and inhibiting colon cancer cells growth. Settings |and Design: The research was conducted in Medical Faculty Universitas Indonesia with experimental design. Methods and Material: FD ethanol extracts was tested in vitro, in silico and in vivo. In vitro test was conducted to human colon cell lines. In vivo test was conducted to Balb/c mice induced with 10 mg/kg azoxymethane (AOM) and dextran sodium sulfate 1% (DSS). The colonic tissue collected was the distal portion. β-catenin expressions in the cytoplasm and nuclei of the epithelial cells of the colon crypt were semi quantitatively assessed using the immunohistochemistry staining on ten visual fields with 400x magnification. Statistical analysis used: SPSS. Results: FD ethanol extracts inhibit the expression of β-catenin in the crypt ephitelial cells of mice colon induced with AOM/DSS. The extracts also inhibit the growth of human colon cancer (HCT 116) with IC50 value of 5.41 mg/mL. Phytochemical screening to the extracts gave three groups of compounds: alkaloid, flavonoid, and tannin. Water fraction is the best fraction. Based on in the results of in silico analysis with molecular docking, FD extract is believed to influence the expression of β-catenin, in which vitexin and isovitexin are the main candidate compounds to influence the expression of the protein. Conclusion: FD ethanol extract is potential to be an anti-colon cancer proven by the extract capability to reduce β-catenin expression.

HOXA3 promotes tumor growth of human colon cancer through activating EGFR/Ras/Raf/MEK/ERK signaling pathway.

Homeobox A3 (HOXA3), one of HOX transcription factors, regulates gene expression during embryonic development. HOXA3 expression has been reported to be associated with several cancers; however, its role in colon cancer and underlying mechanism are still unclear. The expression of HOXA3 in 232 paired of human colon tumor and adjacent non-tumorous tissues were measured by qPCR. The relationship between HOXA3 expression and clinical outcomes were analyzed by Kaplan-Meier survival curves analysis. Human colon cancer cell lines HT29 and HTC116 were transfected with HOXA3 siRNA, or HOXA3 expressing vector, and then cell proliferation and apoptosis were assessed, respectively. Western blot was performed to detect the activation of EGFR/Ras/Raf/MEK/ERK signaling pathway. Moreover, HOXA3-overexpressing and HOXA3-suppressing HT29 cells were subcutaneous injected into nod mice to confirm the regulation of HOXA3 on EGFR/Ras/Raf/MEK/ERK signaling in regulating tumor growth. HOXA3 was upregulated in colon tumor tissues and cell lines, and upregulated expression of HOXA3 was associated with low survival rate. Knockdown of HOXA3 suppressed cell viability and clone formation, while induced cell apoptosis. HOXA3 knockdown could not induce the increase of cell apoptosis on the condition of EGFR overexpression. In vivo xenograft studies, HOXA3-suppressing cells showed less tumorigenic. Moreover, HOXA3 knockdown suppressed the activation of EGFR/Ras/Raf/MEK/ERK signaling pathway. To conclude, this study indicated that HOXA3 might act as a promoter of human colon cancer formation by regulating EGFR/Ras/Raf/MEK/ERK signaling pathway. HOXA3 might be a potential therapeutic target for the treatment of colon cancer.

Chloroform fraction of Scutellaria barbata D.Don inhibits the growth of colorectal cancer cells by activating miR‑34a.

Scutellaria barbata D.Don (SB) is a well known formula in traditional Chinese medicine, which exhibits potent anticancer effects on various cancers. Many miRNAs play crucial roles in the regulation of cancer, for instance, miR‑34a functions as a tumor suppressor, and is often downregulated during cancer. In this study, we investigated the role of ECSB in suppressing the growth of human colon cancer HCT‑8 cells, and whether this is mediated by regulation of miR‑34a and its downstream target genes, using real-time PCR and western blot analysis. ECSB treatment significantly inhibited the proliferation of HCT‑8 cells and promoted apoptosis in a dose-dependent manner. In addition, ECSB treatment significantly increased the level of miR‑34a expression and decreased the levels of Bcl-2, Notch1/2 and Jagged1 expression. Furthermore, knockdown of miR‑34a expression through transfection of anti-miR‑34a oligonucleotide was significantly reversed by ECSB treatment. Likewise, knockdown of miR‑34a resulted in significant upregulation of Bcl-2, Notch1/2 and Jagged1 expression, which was reversed following ECSB treatment. Therefore, this study reveals that ECSB inhibited cancer cell growth via promoting apoptosis and inhibiting proliferation, through regulation of miR‑34a. These findings further support the use of ECSB as an effective therapeutic agent against colon cancer.

Effects of Hylomecon vernalis ethanol extracts on cell cycle and apoptosis of colon cancer cells.

Hylomecon vernalis Maxim. has traditionally been used to promote blood circulation, alleviate pain, dissipate stasis, and reduce swelling. The aim of the present study was to investigate the effect and potential mechanism of H. vernalis Maxim. ethanol extracts (HVMEE) on the growth and apoptosis of human colon cancer HT-29 and SW620 cells. H. vernalis samples were extracted three times with ethanol, dried, and concentrated into powder. The components of HVMEE were investigated using high performance liquid chromatography in tandem with mass spectrometry analysis. MTT assay was used to investigate the effect of HVMEE on viability of human colon cancer HT-29 and SW620 cells. Apoptosis of HT-29 and SW620 cells was evaluated using flow cytometric analysis. Expression levels of apoptosis and cell cycle-related proteins were assessed by western blot. The findings demonstrated that the alkaloid content of HVMEE was as high as 89.67%, and it effectively inhibited viability in HT-29 and SW620 cells, with IC50 values of 0.105±0.022 mg/ml and 0.146±0.013 mg/ml, respectively. In addition, HVMEE induced apoptosis in HT-29 and SW620 cells, by increasing caspase-3, caspase-9 and BCL2 associated X expression, and reducing Bcl-2 expression. The present study suggests that HVMEE has a potential role in the treatment of colorectal cancer.

High-fat Western diet–induced obesity contributes to increased tumor growth in mouse models of human colon cancer

Strong epidemiologic evidence links colon cancer to obesity. The increasing worldwide incidence of colon cancer has been linked to the spread of the Western lifestyle, and in particular consumption of a high-fat Western diet. In this study, our objectives were to establish mouse models to examine the effects of high-fat Western diet–induced obesity on the growth of human colon cancer tumor xenografts, and to examine potential mechanisms driving obesity-linked human colon cancer tumor growth. We hypothesize that mice rendered insulin resistant due to consumption of a high-fat Western diet will show increased and accelerated tumor growth. Homozygous Rag1tm1Mom mice were fed either a low-fat Western diet or a high-fat Western diet (HFWD), then human colon cancer xenografts were implanted subcutaneously or orthotopically. Tumors were analyzed to detect changes in receptor tyrosine kinase–mediated signaling and expression of inflammatory-associated genes in epididymal white adipose tissue. In both models, mice fed an HFWD weighed more and had increased intra-abdominal fat, and tumor weight was greater compared with in the low-fat Western diet–fed mice. They also displayed significantly higher levels of leptin; however, there was a negative correlation between leptin levels and tumor size. In the orthotopic model, tumors and adipose tissue from the HFWD group displayed significant increases in both c-Jun N-terminal kinase activation and monocyte chemoattractant protein 1 expression, respectively. In conclusion, this study suggests that human colon cancer growth is accelerated in animals that are obese and insulin resistant due to the consumption of an HFWD.

Targeting acid sphingomyelinase with anti-angiogenic chemotherapy

Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase+/+, but not in asmase−/−, hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1–2h before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials.

SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin.

SARI, also called as BATF2, belongs to the BATF family and has been implicated in cancer cell growth inhibition. However, the role and mechanism of SARI in tumour angiogenesis are elusive. Here we demonstrate that SARI deficiency facilitates AOM/DSS-induced colonic tumorigenesis in mice. We show that SARI is a novel inhibitor of colon tumour growth and angiogenesis in mice. Antibody array and HUVEC-related assays indicate that VEGF has an essential role in SARI-controlled inhibition of angiogenesis. Furthermore, Co-IP/PAGE/mass spectrometry indicates that SARI directly targets ceruloplasmin (Cp), and induces protease degradation of Cp, thereby inhibiting the activity of the HIF-1α/VEGF axis. Tissue microarray results indicate that SARI expression inversely correlates with poor clinical outcomes in colon cancer patients. Collectively, our results indicate that SARI is a potential target for therapy by inhibiting angiogenesis through the reduction of VEGF expression and is a prognostic indicator for patients with colon cancer.

Abstract 5068: Treatment with regorafenib inhibits the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic nude mice model of colon cancer

Abstract Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to migrate to tumor stroma as well as injured tissue. We reported that, in an orthotopic nude mice model of colon cancer, MSCs travel to tumor stroma and differentiate into carcinoma-associated fibroblasts (CAFs), and then, they promote growth and metastasis of colon cancer. We also found that CAFs express platelet-derived growth factor receptor-beta (PDGFR-β), at a high level and that imatinib therapy targeting PDGFR in CAFs combined with administration of a cytotoxic drug significantly inhibits growth and metastasis of human colon cancer. A novel oral multi-kinase inhibitor, regorafenib not only inhibits oncogenic receptor tyrosine kinases such as c-KIT, RET, and B-RAF, but also inhibits stromal cells which express VEGFR1-3, TIE2, PDGFR-β, and fibroblast growth factor receptor 1 (FGFR1). These cell surface receptor tyrosine kinases are known to be involved in tumor neovascularization, vessel stabilization, lymphatic vessel formation as well as activation of stroma. We examined whether the effect of MSCs on tumor growth and metastasis was inhibited by regorafenib. KM12SM human colon cancer cells alone or KM12SM cells mixed with MSCs in a 1:2 ratio were transplanted into the cecal wall of nude mice. Orthotopic transplantation of KM12SM cells + MSCs, in comparison to transplantation of KM12SM cells alone, resulted in tumors of greater weight and volume, and higher rate of lymphatic metastasis. Co-injection of MSCs with tumor cells promoted tumor growth and metastasis of colon cancer by enhancing angiogenesis, lymphangiogenesis, and tumor cell proliferation and by inhibiting tumor cell apoptosis. When CRC tumor + MSCs bearing animals were treated with regorafenib (by oral gavage once daily at 10 mg/kg for 35 days), primary tumor size or the number of lymph node metastases were significantly decreased compared to those treated with vehicle, and reached to the level with no significant difference from KM12SM tumor cells alone. Our data suggest that targeting tumor microenvironmental signaling pathways by regorafenib influences the interaction between bone marrow-derived MSCs and tumor cells and, hence, inhibits the progressive growth of colon cancer. Citation Format: Kei Shinagawa, Yasuhiko Kitadai, Ryo Yuge, Mieko Onoyama, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Treatment with regorafenib inhibits the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic nude mice model of colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5068. doi:10.1158/1538-7445.AM2015-5068

Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia.

The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors.