Microenvironmental regulation of tumour angiogenesis

Daniela Biziato, Michele De Palma
Nature Publishing Group, 2017
Article

Résumé

Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.

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https://infoscience.epfl.ch/record/229216?ln=fr

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Molecular profiling and functional analysis of macrophage-derived tumour extracellular vesicles

Tim Beltraminelli

Extracellular vesicles (EVs) are nanosized vesicles released by virtually all cell types. Increasing data suggest that EVs function in the regulation of intercellular communication both in physiological and pathological states. In cancer biology, mounting evidence suggests that cancer cell-derived EVs directly modulate several aspects of tumour progression by acting on both cancer cells and tumour-associated stromal cells. In addition to cancer cells, the tumour microenvironment (TME) also features an intertwined ensemble of recruited host-derived cells. Tumour-associated macrophages (TAMs) often infiltrate tumours in high numbers, thus representing one of the major host-derived cell populations. The involvement of TAMs in cancer progression has been extensively documented. It is well established that according to their polarisation state, TAMs can exert both pro- and anti-tumoural functions. However, under the influence of cancer cell-derived factors TAMs often acquire a phenotype that fosters tumour progression by supporting angiogenesis, metastasis and immunosuppression. While the role of secreted soluble factors contributing to the pro- and anti-tumoural functions of TAMs is well characterised, the molecular composition, properties, and effects of TAM-derived EVs (TAM-EVs) in the TME are poorly understood. In this thesis, I studied TAM-EVs produced in intact mouse tumours. We developed a methodology for the enrichment, quantification, and selective isolation of TAM-EVs produced in the TME. Furthermore, we performed comprehensive proteomic and lipidomic analyses of tumour-derived EVs and identified molecular signatures indicative of a role for TAM-EVs in immune response and lipid metabolism. Whereas source TAMs display a phenotype consistent with immunosuppressive functions, TAM-EVs have a pro-inflammatory and immune-stimulatory molecular signature. Indeed, TAM-EV-enriched preparations promoted T-cell proliferation and activation ex vivo and modulated arachidonic acid metabolism of cancer cells by inhibiting the production of the immunosuppressive PGE2 while favouring the secretion of pro-inflammatory thromboxane. Therefore, TAM-EVs might have the potential to stimulate, rather than limit, anti-tumour immunity. I also showed that while portraying some similarities with EVs of in vitro-polarised macrophages, TAM-EVs isolated from the TME present distinctive molecular profiles, suggesting that simplistic in vitro models do not faithfully recapitulate the complexity of the TME dynamics. Overall, this work emphasises the importance of studying TAM-EVs in their physiological context and identifies a potential role for TAM-EVs in favouring the development of an anti-tumoural immune microenvironment. Findings from this work extend our knowledge of the multifaceted role of TAMs in tumour biology.

EPFL2020

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Background Estrogen receptor alpha (ER alpha) signaling is a defining and driving event in most breast cancers; ER alpha is detected in malignant epithelial cells of 75% of all breast cancers (classified as ER-positive breast cancer) and, in these cases, ER alpha targeting is the main therapeutic strategy. However, the biological determinants of ER alpha heterogeneity and the mechanisms underlying therapeutic resistance are still elusive, hampered by the challenges in developing experimental models recapitulative of intra-tumoral heterogeneity and in which ER alpha signaling is sustained. Ex vivo cultures of human breast cancer tissue have been proposed to retain the original tissue architecture, epithelial and stromal cell components and ER alpha. However, loss of cellularity, viability and ER alpha expression are well-known culture-related phenomena. Methods BC samples were collected and brought to the laboratory. Then they were minced, enzymatically digested, entrapped in alginate and cultured for 1 month. The histological architecture, cellular composition and cell proliferation of tissue microstructures were assessed by immunohistochemistry. Cell viability was assessed by measurement of cell metabolic activity and histological evaluation. The presence of ER alpha was accessed by immunohistochemistry and RT-qPCR and its functionality evaluated by challenge with 17-beta-estradiol and fulvestrant. Results We describe a strategy based on entrapment of breast cancer tissue microstructures in alginate capsules and their long-term culture under agitation, successfully applied to tissue obtained from 63 breast cancer patients. After 1 month in culture, the architectural features of the encapsulated tissue microstructures were similar to the original patient tumors: epithelial, stromal and endothelial compartments were maintained, with an average of 97% of cell viability compared to day 0. In ER alpha-positive cases, fibers of collagen, the main extracellular matrix component in vivo, were preserved. ER alpha expression was at least partially retained at gene and protein levels and response to ER alpha stimulation and inhibition was observed at the level of downstream targets, demonstrating active ER signaling. Conclusions The proposed model system is a new methodology to study ex vivo breast cancer biology, in particular ER alpha signaling. It is suitable for interrogating the long-term effects of anti-endocrine drugs in a set-up that closely resembles the original tumor microenvironment, with potential application in pre- and co-clinical assays of ER alpha-positive breast cancer.

2020

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BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins. METHODS AND RESULTS: In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5-AECD; control cells - Panc1-control) significantly increases their invasion in vitro via enhanced ERK phosphorylation. Interestingly, orthotopic injection of Panc1-Sema5A-ECD cells into athymic nude mice results in a lower primary tumour burden, but enhances the micrometastases to the liver as compared with Panc1-control cells. Furthermore, there is a significant increase in proliferation of endothelial cells treated with conditioned media (CM) from Panc1-Sema5A-ECD cells and a significant increase in microvessel density in Panc1-Sema5A-ECD orthotopic tumours compared with those from Panc1-control cells, suggesting that the increase in liver micrometastases is probably due to increased tumour angiogenesis. In addition, our data demonstrate that this increase in endothelial cell proliferation by Sema5A-ECD is mediated through the angiogenic molecules - interleukin-8 and vascular endothelial growth factor. CONCLUSION: Taken together, these results suggest that a bioactive, secreted form of Sema5A-ECD has an intriguing and potentially important role in its ability to enhance pancreatic tumour invasiveness, angiogenesis and micrometastases. British Journal of Cancer (2012) 107, 501-507. doi: 10.1038/bjc.2012.298 www.bjcancer.com Published online 10 July 2012 (C) 2012 Cancer Research UK

Nature Publishing Group2012

Chargement

Molecular profiling and functional analysis of macrophage-derived tumour extracellular vesicles

Tim Beltraminelli

EPFL2020

Nature Publishing Group2012

2020