Interplay between tumor microenvironment and partial EMT as the driver of tumor progression

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

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Hypoxia and the Tumor Microenvironment

Technology in Cancer Research & Treatment ◽

10.1177/15330338211036304 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110363

Author(s):

Yue Li ◽

Long Zhao ◽

Xiao-Feng Li

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Poor Prognosis ◽

Tumor Biology ◽

Metastatic Potential ◽

Tumor Detection ◽

Tumor Aggressiveness

Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.

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Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01124-7 ◽

2021 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Atsuhito Uneda ◽

Kazuhiko Kurozumi ◽

Atsushi Fujimura ◽

Kentaro Fujii ◽

Joji Ishida ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Tumor Cells ◽

In Silico ◽

Tumor Tissue ◽

The Cancer Genome Atlas ◽

Macrophage Infiltration ◽

Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

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KIF18B as a regulator in tumor microenvironment accelerates tumor progression and triggers poor outcome in hepatocellular carcinoma

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2021.106037 ◽

2021 ◽

pp. 106037

Author(s):

Meng-jun Qiu ◽

Li Zhang ◽

Yao-bing Chen ◽

Li-sheng Zhu ◽

Bin Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Poor Outcome

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Starved and Asphyxiated: How Can CD8+ T Cells within a Tumor Microenvironment Prevent Tumor Progression

Frontiers in Immunology ◽

10.3389/fimmu.2016.00032 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 41

Author(s):

Ying Zhang ◽

Hildegund C. J. Ertl

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Cd8 T Cells

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Interstitial flow promotes macrophage polarization toward an M2 phenotype

Molecular Biology of the Cell ◽

10.1091/mbc.e18-03-0164 ◽

2018 ◽

Vol 29 (16) ◽

pp. 1927-1940 ◽

Cited By ~ 22

Author(s):

Ran Li ◽

Jean Carlos Serrano ◽

Hao Xing ◽

Tara A. Lee ◽

Hesham Azizgolshani ◽

...

Keyword(s):

Fluid Flow ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Cell ◽

Interstitial Fluid ◽

Macrophage Polarization ◽

Interstitial Flow ◽

Interstitial Fluid Flow ◽

M2 Polarization ◽

Tumor Tissues

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.

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Trp53 inactivation in the tumor microenvironment promotes tumor progression by enhancing pro-inflammatory tumor stromal populations

Journal for ImmunoTherapy of Cancer ◽

10.1186/2051-1426-1-s1-p189 ◽

2013 ◽

Vol 1 (Suppl 1) ◽

pp. P189

Author(s):

Gang Guo ◽

Luis Marrero ◽

Augusto Ochoa ◽

Yan Cui

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression

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NIR Bioluminescence Probe Enables Discovery of Diet-Induced Modulation of the Tumor Microenvironment via Nitric Oxide

10.26434/chemrxiv.14176835.v1 ◽

2021 ◽

Author(s):

Anuj K Yadav ◽

Michael C. Lee ◽

Melissa Lucero ◽

Christopher J. Reinhardt ◽

ShengZhang Su ◽

...

Keyword(s):

Nitric Oxide ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Critical Role ◽

Cellular Systems ◽

Tissue Imaging ◽

Molecular Evidence ◽

No Production ◽

The Impact

Nitric oxide (NO) plays a critical role in acute and chronic inflammation. NO’s contributions to cancer are of particular interest due to its context-dependent bioactivities. For example, immune cells initially produce cytotoxic quantities of NO in response to the nascent tumor. However, it is believed that this fades over time and reaches a concentration that supports the tumor microenvironment (TME). These complex dynamics are further complicated by other factors, such as diet and oxygenation, making it challenging to establish a complete picture of NO’s impact on tumor progression. Although many activity-based sensing (ABS) probes for NO have been developed, only a small fraction have been employed in vivo and fewer yet are practical in cancer models where the NO concentration is < 200 nM. To overcome this outstanding challenge, we have developed BL660-NO, the first ABS probe for NIR bioluminescence imaging of NO in cancer. Owing to the low intrinsic background, high sensitivity, and deep tissue imaging capabilities of our design, BL660-NO was successfully employed to visualize endogenous NO in cellular systems, a human liver metastasis model, and a murine breast cancer model. Importantly, its exceptional performance facilitated the design of a dietary study to examine the impact of NO on the TME by varying the intake of fat. BL660-NO provides the first direct molecular evidence that intratumoral NO becomes elevated in mice fed a high-fat diet who became obese with larger tumors compared to control animals on a low-fat diet. These results indicate that an inflammatory diet can increase NO production via recruitment of macrophages and overexpression of iNOS which in turn can drive tumor progression.

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