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

Published on Sep 1, 2020in Proceedings of the National Academy of Sciences of the United States of America9.412
· DOI :10.1073/PNAS.2008112117
Yoshiro Itatani16
Estimated H-index: 16
(UCSD: University of California, San Diego),
Takamasa Yamamoto5
Estimated H-index: 5
(UCSD: University of California, San Diego)
+ 5 AuthorsNapoleone Ferrara179
Estimated H-index: 179
(UCSD: University of California, San Diego)
Source
Abstract
We tested cis-ApcΔ716/Smad4+/− and cis-ApcΔ716/Smad4+/−KrasG12D mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-ApcΔ716/Smad4+/−KrasG12D mice, 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) in cis-ApcΔ716/Smad4+/− and cis-ApcΔ716/Smad4+/−KrasG12D mice 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.
📖 Papers frequently viewed together
110 Citations
6 Authors (Jibin Li, ..., Rui Zhang)
26 Citations
References59
Newest
Abstract Background The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinom...
489 CitationsSource
#1Rajendra S. Apte (WashU: Washington University in St. Louis)H-Index: 37
#2Daniel S. ChenH-Index: 40
Last. Napoleone Ferrara (UCSD: University of California, San Diego)H-Index: 179
view all 3 authors...
The discovery of vascular endothelial-derived growth factor (VEGF) has revolutionized our understanding of vasculogenesis and angiogenesis during development and physiological homeostasis. Over a short span of two decades, our understanding of the molecular mechanisms by which VEGF coordinates neurovascular homeostasis has become more sophisticated. The central role of VEGF in the pathogenesis of diverse cancers and blinding eye diseases has also become evident. Elucidation of the molecular regu...
274 CitationsSource
#1Wei Liang (UCSD: University of California, San Diego)H-Index: 10
#2Qin Li (UCSD: University of California, San Diego)H-Index: 6
Last. Napoleone Ferrara (UCSD: University of California, San Diego)H-Index: 179
view all 3 authors...
The tumor-promoting functions of neutrophils have been mainly attributed to induction of tumor angiogenesis or suppression of anticancer immunity. However, a direct impact of neutrophils on tumor cell growth and metastasis remains largely uncharacterized. Here, we coupled a proteomic approach with a functional screen to interrogate the secretome of tumor-associated neutrophils. Surprisingly, the iron-transporting protein transferrin was identified as the major mitogen for tumor cells secreted by...
23 CitationsSource
#1Mark A. SocinskiH-Index: 76
#2Robert M. JotteH-Index: 22
Last. Martin ReckH-Index: 71
view all 20 authors...
Abstract Background The cancer-cell–killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor–mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non–small-cell lung cancer (NSCLC) who had not previously received chemotherapy. Methods We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), beva...
1,103 CitationsSource
The mammalian prokineticins family comprises two conserved proteins, EG-VEGF/PROK1 and Bv8/PROK2, and their two highly related G protein-coupled receptors, PKR1 and PKR2. This signaling system has been linked to several important biological functions, including gastrointestinal tract motility, regulation of circadian rhythms, neurogenesis, angiogenesis and cancer progression, hematopoiesis, and nociception. Mutations in PKR2 or Bv8/PROK2 have been associated with Kallmann syndrome, a development...
20 CitationsSource
#1Valeria Governa (University of Basel)H-Index: 7
#2Emanuele Trella (University of Basel)H-Index: 10
Last. Giulio C. Spagnoli (University of Basel)H-Index: 69
view all 17 authors...
Abstract Purpose: Tumor infiltration by different T lymphocyte subsets is known to be associated with favorable prognosis in colorectal cancer (CRC). Still debated is the role of innate immune system. We investigated clinical relevance, phenotypes and functional features of CRC infiltrating CD66b+ neutrophils and their crosstalk with CD8+ T cells. Experimental design: CD66b+ and CD8+ cell infiltration was analyzed by immunohistochemistry on a tissue microarray including >650 evaluable CRC sample...
69 CitationsSource
#1Ting-ting Wang (Third Military Medical University)H-Index: 13
#2Yongliang Zhao (Third Military Medical University)H-Index: 18
Last. Quanming Zou (Third Military Medical University)H-Index: 34
view all 16 authors...
Objective Neutrophils are prominent components of solid tumours and exhibit distinct phenotypes in different tumour microenvironments. However, the nature, regulation, function and clinical relevance of neutrophils in human gastric cancer (GC) are presently unknown. Design Flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 105 patients with GC. Kaplan-Meier plots for overall survival were performed using the log-rank test. Neutrophils and T cell...
127 CitationsSource
Myeloid cells developed evolutionarily as a major mechanism to protect the host. They evolved as a critical barrier against infections and are important contributors to tissue remodeling. However, in cancer, myeloid cells are largely converted to serve a new master—tumor cells. This process is epitomized by myeloid-derived suppressor cells (MDSC). These cells are closely related to neutrophils and monocytes. MDSCs are not present in the steady state of healthy individuals and appear in cancer an...
592 CitationsSource
#1Jeffrey Wallin (Genentech)H-Index: 24
#2Johanna C. Bendell (Sarah Cannon Research Institute)H-Index: 69
Last. David F. McDermott (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 93
view all 22 authors...
Cancer immunotherapy can be used in combination with other therapies for a better response. Here, the authors conduct a phase Ib clinical study and report the clinical activity and the immune response of the anti-PDL1 agent, atezolizumab, in combination with bevacizumab in ten patients with metastatic renal cell carcinoma.
287 CitationsSource
#1Gordon C Jayson (University of Manchester)H-Index: 72
#2Robert S. Kerbel (Sunnybrook Research Institute)H-Index: 123
Last. Adrian L. Harris (University of Oxford)H-Index: 191
view all 4 authors...
Summary Angiogenesis, the formation of new blood vessels from pre-existing vessels, has been validated as a target in several tumour types through randomised trials, incorporating vascular endothelial growth factor (VEGF) pathway inhibitors into the therapeutic armoury. Although some tumours such as renal cell carcinoma, ovarian and cervical cancers, and pancreatic neuroendocrine tumours are sensitive to these drugs, others such as prostate cancer, pancreatic adenocarcinoma, and melanoma are res...
389 CitationsSource
Cited By2
Newest
#1Sana Hibino (UTokyo: University of Tokyo)H-Index: 1
Last. Koji TaniguchiH-Index: 31
view all 7 authors...
Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as he...
Source
Colorectal cancer (CRC) is one of the most common malignancy and cause of cancer death worldwide, and it still remains a therapeutic challenge for western medicine. There is strong evidence that, in addition to genetic predispositions, environmental factors have also a substantial impact in CRC development. The risk of CRC is attributed, among others to dietary habits, alcohol consumption, whereas physical activity, food containing dietary fiber, dairy products, and calcium supplements have a pr...
Source
#1Wei LiangH-Index: 10
#2Napoleone Ferrara (UCSD: University of California, San Diego)H-Index: 179
Cells of the innate immune system are a major component of the tumor microenvironment. They play complex and multifaceted roles in the regulation of cancer initiation, growth, metastasis and responses to therapeutics. Innate immune cells like neutrophils and macrophages are recruited to cancerous tissues by chemotactic molecules released by cancer cells and cancer-associated stromal cells. Once they reach the tumor, they can be instructed by a network of proteins, nucleic acids and metabolites t...
Source