Glucose transporters in cancer - from tumor cells to the tumor microenvironment

Solute carriers of the glucose transporter (GLUT) family mediate the first step for cellular glucose usage. The upregulation of GLUTs has been reported in numerous cancer types as a result of perturbation of gene expression or protein relocalization or stabilization. Because they enable to sustain the energy demand required by tumor cells for various biochemical programs, they are promising targets for the development of anticancer strategies. Recently, important biological insights have come from the fine crystal structure determination of several GLUTs; these advances will likely catalyze the development of new selective inhibitory compounds. Furthermore, deregulated glucose metabolism of nontumor cells in the tumor mass is beginning to be appreciated and could have major implications for our understanding of how glucose uptake by specific cell types influences the behavior of neighboring cells in the same microenvironment. In this review, we discuss some of the deregulation mechanisms of glucose transporters, their genetic and pharmacological targeting in cancer, and new functions they may have in nontumor cells of the tumor environment or beyond glucose uptake for glycolysis.

Gene expression analysis of metastases and IL-1R1 characterization in a NALP3 mouse model

Heidi Fournier

Tumor microenvironment contributes strongly to tumor evolution toward metastasis, a final stage in cancer progression. It provides essential clues to promote migration of cancer cells in metastatic sites. Moreover, inflammatory cells and immunomodulatory mediators present in the microenvironment are able to polarize the host immune response, thereby potentiating primary tumor development. The reciprocal and dynamic interactions between microenvironment and tumor cells orchestrate critical steps of evolution toward metastasis. To address the role of inflammation in tumor progression, a mouse model of downregulated inflammation was used: the NALP3 gene in these mice is knocked-out, causing a impaired processing of the two inflammatory cytokines Interleukin-1[beta] and IL-18 which are essential for the recruitment and activation of immune cells. In this case, a decrease in tumor growth and metastasis was observed in previous studies, leading us to investigate the molecular and cellular interactions of tumor and immune cells in inflammatory and non-inflammatory contexts. Gene expression analysis was performed on two steps of mouse tumor cells: the B16-F10 melanoma cells seem to be more dependent on the immune cells recruitment to metastasize in vivo, while the Lewis Lung Carcinomas cells showed a quite equivalent growth in both wild-type or NALP3 knock-out mice. Different techniques were used to do so, such as standard in vitro assays and mRNA expression analyses, and in vivo tests with extraction of tumoral mRNA by Laser Capture Microdissection. Gene expression analyses of tumor cells were performed to address the influence of the inflammatory background. Comparison of these two gene expression profiles may reveal genes related to the specific reactive inflammatory response surrounding the given metastases. Another point that was investigated was the importance of the IL-1R1, receptor of interleukin-1. Since it represents the counterpart of IL-1[beta] signaling, its expression by immune and tumor cells may correlate with degree of tumor growth and invasion. In vitro and in vivo assays allowed better understanding the importance of this receptor. While a downregulation of this receptor impairs proliferation of in vitro cell cultures, at the in vivo level, the number of metastases is decreased too. These results provide potential clues indicating the important role played by the inflammatory cells, and how they can support and promote tumor progression, in particular through the expression of NALP3. The adaptation mechanisms of tumor cells to their microenvironment were also assessed, opening different insights for targeting the tumor itself as well as the inflammatory microenvironment.

2011

New roles of the lymphatic endothelium in modulating adaptive immunity: implications for immune tolerance and cancer immunotherapy

Lambert Charles François Potin

Lymphatic vessels have traditionally been considered as passive conduits for interstitial fluid drainage and for immune cell trafficking to lymph nodes. In the last two decades, many studies have challenged this classical dogma: lymphatic endothelial cells (LECs) were shown to actively interact with immune cells by secreting chemokines and cytokines, and presenting antigens to T cells. These newly described functions pinpoint a multi-faceted role of LECs in orchestrating the immune response through both passive and active mechanisms. Yet, precise mechanisms leading to antigen-specific fine-tuning of the T cell response remain unexplored. Moreover, although lymphatics have been shown to play important roles in cancer, the contributions of LECs in regulating antitumor immunity have been largely overlooked by the biomedical community. This doctoral thesis aimed at filling these gaps. First, in order to investigate the mechanisms and implications of LEC antigen presentation to CD4+ T cells, we engineered a mouse model where LECs lacked the ability to present antigens to CD4+ T cells. In these mice, antigen-specific responses to vaccination were increased when compared to wild-type controls. Moreover, we demonstrated that LECs were poor inducers of CD4+ T cell activation in vitro, and that they could dampen CD4+ T cell activation by dendritic cells. Taken together, these findings suggest that LECs participate to the peripheral immune tolerance of CD4+ T cells. Second, we investigated the immunological consequences of the development of lymphatic vessels, called lymphangiogenesis, in mouse melanoma. Upon induction of tumor lymphangiogenesis, we observed striking tumor enrichment with immune cells, which resulted in a higher sensitivity of those tumors to immunotherapy. We subsequently demonstrated that inducing lymphangiogenesis in a mouse model of cold tumors, which lack immune infiltrates and do not respond to immunotherapies, could restore their responsiveness to immunotherapy treatments. Third, to predict which cancer types were the most likely to replicate the findings we obtained in mouse melanoma, we mined The Cancer Genome Atlas database for gene expression. We identified a set of cancers, such as colon adenocarcinoma and cholangiocarcinoma, where high expression of the lymphangiogenic growth factor was associated with a strong T cell signature. This doctoral thesis unveiled new immunomodulatory functions of LECs by which antigen-specific immune tolerance is induced. Additionally, it opened new avenues to target lymphatics therapeutically in cancer to potentiate immunotherapies. We believe this work contributes to demonstrating the immunological importance of LECs, and hope that lymphatics will be considered as an important immunomodulatory player of the tumor microenvironment when developing novel immunotherapies.

EPFL2018

Macrophage regulation of tumor angiogenesis: implications for cancer therapy

Michele De Palma, Mario Leonardo Squadrito

This article reviews the evidence for macrophages playing an important role in the regulation of tumor angiogenesis. Findings in mouse models show that macrophages promote angiogenesis in tumors both by producing excessive amounts of proangiogenic factors and by physically assisting sprouting blood vessels to augment the complexity of the intra-tumoral vascular network. Recent studies however suggest that macrophages may be dispensable for the initiation of angiogenesis in tumors. Rather, these cells express proangiogenic programs that enhance the complexity of the tumor-associated vasculature, leading to aberrant, plethoric and dysfunctional angiogenesis. Gene expression and cell depletion studies further indicate that tumor-associated macrophages (TAMs) comprise phenotypically and functionally distinct subsets. This may reflect "education" of the macrophage phenotype by signals in some areas of the tumor microenvironment and/or TAM subsets derived from distinct macrophage precursors. Among the better characterized TAM subsets are the proangiogenic (TIE2(+)) and the angiostatic/inflammatory (CD11c(+)) macrophages, which coexist in tumors. Such antagonizing TAM subsets occupy distinct niches in the tumor microenvironment and are present at ratios that vary according to the tumor type and grade. Specifically targeting TAMs or reprogramming them from a proangiogenic to an angiostatic function may "normalize" the tumor vasculature and improve the efficacy of various anticancer therapies, including radiotherapy, chemotherapy and vascular-disrupting agents.

2011

New roles of the lymphatic endothelium in modulating adaptive immunity: implications for immune tolerance and cancer immunotherapy

Lambert Charles François Potin

EPFL2018

Gene expression analysis of metastases and IL-1R1 characterization in a NALP3 mouse model

Heidi Fournier

2011