Optical Windows for Imaging the Metastatic Tumour Microenvironment in vivo

Abstract Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.

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Tumour vessel remodelling: new opportunities in cancer treatment

Vascular Biology ◽

10.1530/vb-19-0032 ◽

2020 ◽

Vol 2 (1) ◽

pp. R35-R43

Author(s):

Ruth Ganss

Keyword(s):

Tumour Microenvironment ◽

Metastatic Tumour ◽

Full Potential ◽

Functional Rehabilitation ◽

Angiogenic Therapy ◽

Transient Nature ◽

Tumour Vasculature ◽

Attractive Therapeutic Target ◽

Tumour Vessel

Tumour growth critically depends on a supportive microenvironment, including the tumour vasculature. Tumour blood vessels are structurally abnormal and functionally anergic which limits drug access and immune responses in solid cancers. Thus, tumour vasculature has been considered an attractive therapeutic target for decades. However, with time, anti-angiogenic therapy has evolved from destruction to structural and functional rehabilitation as understanding of tumour vascular biology became more refined. Vessel remodelling or normalisation strategies which alleviate hypoxia are now coming of age having been shown to have profound effects on the tumour microenvironment. This includes improved tumour perfusion, release from immune suppression and lower metastasis rates. Nevertheless, clinical translation has been slow due to challenges such as the transient nature of current normalisation strategies, limited in vivo monitoring and the heterogeneity of primary and/or metastatic tumour environments, calling for more tailored approaches to vascular remodelling. Despite these setbacks, harnessing vascular plasticity provides unique opportunities for anti-cancer combination therapies in particular anti-angiogenic immunotherapy which are yet to reach their full potential.

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Faculty Opinions recommendation of In vivo discovery of immunotherapy targets in the tumour microenvironment.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718256973.793493750 ◽

2014 ◽

Author(s):

Benoit Van den Eynde

Keyword(s):

Tumour Microenvironment

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Apoptosis, cell proliferation and in vivo biological behaviour of primary and metastatic tumour cells of an AKR lymphoma variant

APOPTOSIS ◽

10.1023/a:1026424817392 ◽

1997 ◽

Vol 2 (2) ◽

pp. 214-220 ◽

Cited By ~ 2

Author(s):

N. Donin ◽

D. Katzenelson ◽

J. Ravia ◽

J. Hiss ◽

G. Schiby ◽

...

Keyword(s):

Cell Proliferation ◽

Tumour Cells ◽

Metastatic Tumour ◽

Biological Behaviour

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Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Gut ◽

10.1136/gutjnl-2018-317570 ◽

2018 ◽

Vol 68 (4) ◽

pp. 693-707 ◽

Cited By ~ 18

Author(s):

Delphine Goehrig ◽

Jérémy Nigri ◽

Rémi Samain ◽

Zhichong Wu ◽

Paola Cappello ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumour Growth ◽

Matrix Protein ◽

Immune Escape ◽

Interaction Mechanism ◽

Tumour Microenvironment ◽

Extracellular Matrix Protein ◽

Ductal Adenocarcinoma ◽

The Impact

ObjectivePancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.DesignWe performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.ResultsWe identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.ConclusionsOur data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.

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EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3

Molecular Cancer ◽

10.1186/s12943-021-01485-6 ◽

2022 ◽

Vol 21 (1) ◽

Author(s):

Ziwen Pan ◽

Rongrong Zhao ◽

Boyan Li ◽

Yanhua Qi ◽

Wei Qiu ◽

...

Keyword(s):

Rna Binding ◽

Binding Protein ◽

Expression Profiles ◽

Tumour Microenvironment ◽

Malignant Progression ◽

Luciferase Reporter ◽

Sequencing Analysis ◽

Glioma Progression

Abstract Background Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours. Methods CircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted. Results We identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression. Conclusions This work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.

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Recapitulating tumour microenvironment in chitosan–gelatin three-dimensional scaffolds: an improved in vitro tumour model

Journal of The Royal Society Interface ◽

10.1098/rsif.2012.0564 ◽

2012 ◽

Vol 9 (77) ◽

pp. 3288-3302 ◽

Cited By ~ 29

Author(s):

Neha Arya ◽

Viren Sardana ◽

Meera Saxena ◽

Annapoorni Rangarajan ◽

Dhirendra S. Katti

Keyword(s):

Cancer Progression ◽

Expression Profiles ◽

Three Dimensional ◽

Gene Expression Profiles ◽

Petri Dish ◽

Tumour Microenvironment ◽

Two Dimensional ◽

Tumour Model

Owing to the reduced co-relationship between conventional flat Petri dish culture (two-dimensional) and the tumour microenvironment, there has been a shift towards three-dimensional culture systems that show an improved analogy to the same. In this work, an extracellular matrix (ECM)-mimicking three-dimensional scaffold based on chitosan and gelatin was fabricated and explored for its potential as a tumour model for lung cancer. It was demonstrated that the chitosan–gelatin (CG) scaffolds supported the formation of tumoroids that were similar to tumours grown in vivo for factors involved in tumour-cell–ECM interaction, invasion and metastasis, and response to anti-cancer drugs. On the other hand, the two-dimensional Petri dish surfaces did not demonstrate gene-expression profiles similar to tumours grown in vivo . Further, the three-dimensional CG scaffolds supported the formation of tumoroids, using other types of cancer cells such as breast, cervix and bone, indicating a possible wider potential for in vitro tumoroid generation. Overall, the results demonstrated that CG scaffolds can be an improved in vitro tool to study cancer progression and drug screening for solid tumours.

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700: Confocal fluorescence endomicroscopy in vivo for the detection of tumour microenvironment and healthy tissue margin

European Journal of Cancer ◽

10.1016/s0959-8049(14)50618-1 ◽

2014 ◽

Vol 50 ◽

pp. S168-S169

Author(s):

S.P. Johnson ◽

C. Schneider ◽

A. Desjardins ◽

S. Walker-Samuel ◽

D. Hawkes

Keyword(s):

Tumour Microenvironment ◽

Healthy Tissue ◽

Confocal Fluorescence

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Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

10.1101/248807 ◽

2018 ◽

Author(s):

Carlos R. Figueiredo ◽

Ricardo A. Azevedo ◽

Sasha Mousdell ◽

Pedro T. Resende-Lara ◽

Lucy Ireland ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Metastatic Melanoma ◽

Immune Cells ◽

Tumour Microenvironment ◽

Innate Immune ◽

Innate Immune Cells ◽

Adaptive Immune Cells ◽

Cancer Immunotherapies

ABSTRACTMounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells’ immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

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Bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signaling pathway

10.21203/rs.3.rs-222601/v1 ◽

2021 ◽

Author(s):

Ke Xu ◽

Kai Fang ◽

Yueping Zhan ◽

Yuqian Wang ◽

Chengqi Wu ◽

...

Keyword(s):

Colorectal Cancer ◽

Endothelial Cells ◽

Tumor Microenvironment ◽

Signaling Pathway ◽

Umbilical Vein ◽

Tumour Microenvironment ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

Abstract Background Anti-angiogenesis therapy has increasingly become an important strategy for the treatment of colorectal cancer. Recent studies have shown that tumor microenvironment (TME) promotes tumour angiogenesis. Bufalin is an active compound whose anti-tumor efficacy has been proven by previous studies. However, there are very few studies on the anti-angiogenic effects of bufalin. Methods Herein, human umbilical vein endothelial cells (HUVEC) tube formation, migration and adhesion test were used to assess angiogenesis in vitro. Western blot and quantitative PCR were used to detect relevant protein levels and the expressions of mRNAs. Subcutaneous xenograft tumor model and hepatic metastasis model in mice were established to investigate the influence of bufalin on angiogenesis-mediated by TME in vivo. Results We found that the angiogenesis mediated by tumor microenvironment cells was significantly inhibited in the present of bufalin. The results demonstrated that the pro-angiogenic gene in HUVEC such as VEGF, PDGFA, E-selectin and P-selectin were downregulated by bufalin, and the downregulation was regulated by inhibiting the STAT3 pathway. Overexpression STAT3 could reverse the inhibitory effect of bufalin on angiogenesis. What is more, few reduction of angiogenesis when bufalin directly acted on tumor microenvironment cells. Conclusion Our findings demonstrate that bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signaling pathway of vascular endothelial cells, which reveals that bufalin may be used as a new anti-angiogenic adjuvant therapy medicine in the treatment of colorectal cancer.

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