scholarly journals Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer

2020 ◽  
Vol 117 (35) ◽  
pp. 21598-21608
Author(s):  
Yoshiro Itatani ◽  
Takamasa Yamamoto ◽  
Cuiling Zhong ◽  
Alfredo A. Molinolo ◽  
Jane Ruppel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Risk Factor ◽  
Genetic Model ◽  
Myeloid Cell ◽  
High Plasma ◽  
Anti Vegf ◽  
Chemically Induced ◽  
Genetic Abnormalities ◽  
Metastasis Models

We testedcis-ApcΔ716/Smad4+/−andcis-ApcΔ716/Smad4+/−KrasG12Dmice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors incis-ApcΔ716/Smad4+/−KrasG12Dmice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) incis-ApcΔ716/Smad4+/−andcis-ApcΔ716/Smad4+/−KrasG12Dmice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents.

scholarly journals Subsequent anti-VEGF therapy after first-line anti-EGFR therapy improved overall survival of patients with metastatic colorectal cancer

2018 ◽  
Vol Volume 11 ◽  
pp. 465-471 ◽  
Author(s):  
Tianzhu Qiu ◽  
Wensen Chen ◽  
Ping Li ◽  
Jing Sun ◽  
Yanhong Gu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
First Line ◽  
Anti Vegf

Emodin reduces tumor burden by diminishing M2-like macrophages in colorectal cancer

2022 ◽  
Author(s):  
Alexander T Sougiannis ◽  
Brandon N. VanderVeen ◽  
Ioulia Chatzistamou ◽  
Jason L Kubinak ◽  
Mitzi Nagarkatti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Model ◽  
Tumor Burden ◽  
M1 Macrophages ◽  
Chemically Induced ◽  
Poor Understanding ◽  
Exposed Bone ◽  
The Impact ◽  
Nos2 Expression

Emodin, a natural anthraquinone, has been shown to have anti-tumorigenic properties and may be an effective therapy for colorectal cancer (CRC). However, its clinical development has been hampered by a poor understanding of its mechanism of action. The purpose of this study was to 1) evaluate the efficacy of emodin in mouse models of intestinal/colorectal cancer and 2) to examine the impact of emodin on macrophage behavior in the context of CRC. We utilized a genetic model of intestinal cancer (ApcMin/+) and a chemically induced model of CRC (AOM/DSS). Emodin was administered orally (40 mg/kg or 80 mg/kg in AOM/DSS and 80mg/kg in ApcMin/+) 3x/week to observe its preventative effects. Emodin reduced polyp count and size in both rodent models (p<0.05). We further analyzed the colon microenvironment of AOM/DSS mice and found that mice treated with emodin exhibited lower pro-tumorigenic M2-like macrophages and a reduced ratio of M2/M1 macrophages within the colon (p<0.05). Despite this, we did not detect any significant changes in M2-associated cytokines (IL10, IL4, and Tgfb1) nor M1-associated cytokines (IL6, TNFα, IL1β, and IFNγ) within excised polyps. However, there was a significant increase in NOS2 expression (M1 marker) in mice treated with 80 mg/kg emodin (p<0.05). To confirm emodin's effects on macrophages, we exposed bone marrow-derived macrophages (BMDMs) to C26 colon cancer cell conditioned media. Supporting our in vivo data, emodin reduced M2-like macrophages. Overall, these data support the development of emodin as a natural compound for prevention of CRC given its ability to target pro-tumor macrophages.

scholarly journals Three-dimensional length from the center of the liver is a prognostic factor of colorectal cancer with liver metastasis: a retrospective analysis

2020 ◽  
Author(s):  
Jun Woo Bong ◽  
Yeonuk Ju ◽  
Jihyun Seo ◽  
Sang Hee Kang ◽  
Pyoung-Jae Park ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Overall Survival ◽  
Risk Factor ◽  
Liver Metastasis ◽  
Resection Margin ◽  
Cox Regression ◽  
Significant Risk ◽  
Positive Resection Margin ◽  
Cox Regression Analysis

Abstract Background Resectability of liver metastasis is important to establish a treatment strategy for colorectal cancer patients. We aimed to evaluate the effect of distance from metastasis to the center of the liver on the resectability and patient outcomes after hepatectomy.Methods Clinical data of a total of 124 patients who underwent hepatectomy for colorectal cancer with liver metastasis were retrospectively reviewed. We measured the minimal length from metastasis to the bifurcation of the portal vein at the primary branch of the Glissonean tree and defined it as “Centrality”. Predictive effects on positive resection margin and overall survival of centrality were statistically analyzed.Results The value as a predictive factor for the positive resection margin of centrality was analyzed by the receiver operating characteristic curve (area under the curve = 0.72, P<0.001) and centrality ≤ 1.5 cm was an independent risk factor the positive resection margin in multivariate analysis. Total number of metastases ≥ 3 and centrality ≤ 1.5 cm were significant risk factors of overall survival after Cox regression analysis. Patients with these two risk factors (n=21) had worse 5-year overall survival (10.7%) than patients with one (n=35, 58.3%) or no risk factor (n=68, 69.2%).Conclusion Centrality was related with the positive resection margin of deeply located liver metastasis. Centrality should be considered to establish the surgical strategy for patients with advanced colorectal cancer with liver metastasis.

scholarly journals Increased Epithelial Oxygenation Links Colitis to an Expansion of Tumorigenic Bacteria

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Stephanie A. Cevallos ◽  
Jee-Yon Lee ◽  
Connor R. Tiffany ◽  
Austin J. Byndloss ◽  
Luana Johnston ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Escherichia Coli ◽  
Risk Factor ◽  
Microbial Community ◽  
Intestinal Inflammation ◽  
Aerobic Respiration ◽  
Content Type ◽  
E Coli ◽  
Chemically Induced ◽  
Underlying Mechanisms

ABSTRACT Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of Escherichia coli within the gut-associated microbial community through aerobic respiration. An aerobic expansion of colibactin-producing E. coli was required for the cancer-inducing activity of this pathobiont in a mouse model of colitis-associated colorectal cancer formation. We conclude that increased epithelial oxygenation in the colon is associated with an expansion of a prooncogenic driver species, thereby increasing the cancer-inducing activity of the microbiota. IMPORTANCE One of the environmental factors important for colorectal cancer formation is the gut microbiota, but the habitat filters that control its cancer-inducing activity remain unknown. Here, we show that chemically induced colitis elevates epithelial oxygenation in the colon, thereby driving an expansion of colibactin-producing Escherichia coli, a prooncogenic driver species. These data suggest that elevated epithelial oxygenation is a potential risk factor for colorectal cancer formation because the consequent changes in the gut habitat escalate the cancer-inducing activity of the microbiota.

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