Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases

Frentzas, Sophia; Simoneau, Ève; Bridgeman, Victoria L.; Vermeulen, Peter B.; Foo, Shane; Kostaras, Eleftherios; Nathan, Mark R.; Wotherspoon, Andrew; Gao, Zu-Hua; Shi, Yu; Eynden, Gert Van den; Daley, Frances; Peckitt, Clare; Tan, Xianming; Salman, Ayat; Lazaris, Anthoula; Gazinska, Patrycja; Berg, Tracy J.; Eltahir, Zakaria; Ritsma, Laila; Rheenen, Jacco van; Khashper, Alla; Brown, Gina; Nyström, Hanna; Sund, Malin; Laere, Steven Van; Loyer, Evelyne M.; Dirix, Luc; Cunningham, David; Metrakos, Peter; Reynolds, Andrew R.

doi:10.1038/nm.4197

Cited by 380 publications

(552 citation statements)

References 61 publications

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“…This was documented in a recent study showing that CRCLM with a ‘replacement’ GP resulting from vessel co-option are resistant to, and respond poorly to anti-angiogenic therapy (79). Patient stratification based on the histological GP of their LM may therefore be essential to optimize the benefit from anti-angiogenic therapies (18, 80).…”

Section: B Clinical-translational Advancesmentioning

confidence: 84%

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

Milette

Sicklick

Lowy

et al. 2017

Clinical Cancer Research

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Curative treatment for metastatic solid cancers remains elusive. The liver, which is nourished by a rich blood supply from both the arterial and portal venous systems is the most common site of visceral metastases, particularly from cancers arising in the gastrointestinal (GI) tract, with colorectal cancer (CRC) being the predominant primary site in Western countries. A mounting body of evidence suggests that the liver microenvironment (LME) provides autocrine and paracrine signals originating from both parenchymal and non-parenchymal cells, that collectively create both pre-and pro-metastatic niches for the development of hepatic metastases. These resident cells and their molecular mediators represent potential therapeutic targets for the prevention and/or treatment of liver metastases (LM). This review summarizes: 1) the current therapeutic options for treating LM with a particular focus on CRC LM (CRCLM); 2) the role of the LME in LM at each of its phases 3) potential targets in the LME identified through pre-clinical and clinical investigations and 4) potential therapeutic approaches for targeting elements of the LME before and/or after the onset of LM, as the basis for future clinical trials.

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Section: B Clinical-translational Advancesmentioning

confidence: 84%

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

Milette

Sicklick

Lowy

et al. 2017

Clinical Cancer Research

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“…Vessel co-option has been proposed as an intrinsic or acquired resistance mechanism to anti-angiogenesis (Carmeliet and Jain, 2011; di Tomaso et al, 2011; Emblem and Jain, 2016; Frentzas et al, 2016; Pezzella and Gatter, 2015). Our findings indicate a “glial switch” and Wnt7 signaling as targets in this regard because prolonged anti-VEGF therapy in a mouse model selected for strong upregulation of Olig2 and Wnt7.…”

Section: Discussionmentioning

confidence: 99%

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

et al. 2018

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SUMMARY Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions.

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“…n = 3 biological repeats with three CDMs per condition and per repeat and five FOVs per CDM. ( F ) Schematic representation of fluid shear stress assay, adapted from (63). ( G ) Quantification of cell attachment onto CDMs, growth, and apoptosis after shear stress for KPC cells ± Fasudil pretreatment.…”

Section: Figmentioning

confidence: 99%

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Vennin¹,

Chin²,

Warren³

et al. 2017

Sci. Transl. Med.

225

240

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The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or “priming,” using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

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Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases

Cited by 380 publications

References 61 publications

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

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