Critical Role of Tumor Microenvironment in Shaping NK Cell Functions: Implication of Hypoxic Stress

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

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The Emerging Role of GC-MSCs in the Gastric Cancer Microenvironment: From Tumor to Tumor Immunity

Stem Cells International ◽

10.1155/2019/8071842 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Zhaoji Pan ◽

Yiqing Tian ◽

Guoping Niu ◽

Chengsong Cao

Keyword(s):

Gastric Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Wound Repair ◽

Critical Role ◽

The Novel ◽

Potential Biomarker ◽

Underlying Mechanisms ◽

Gastric Cancer Progression

Mesenchymal stem cells (MSCs) have been declared to not only participate in wound repair but also affect tumor progression. Tumor-associated MSCs, directly existing in the tumor microenvironment, play a critical role in tumor initiation, progression, and development. And different tumor-derived MSCs have their own unique characteristics. In this review, we mainly describe and discuss recent advances in our understanding of the emerging role of gastric cancer-derived MSC-like cells (GC-MSCs) in regulating gastric cancer progression and development, as well as the bidirectional influence between GC-MSCs and immune cells of the tumor microenvironment. Moreover, we also discuss the potential biomarker and therapeutic role of GC-MSCs. It is anticipated that new and deep insights into the functionality of GC-MSCs and the underlying mechanisms will promote the novel and promising therapeutic strategies against gastric cancer.

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Metabolic Switching of Mycobacterium tuberculosis during Hypoxia Is Controlled by the Virulence Regulator PhoP

Journal of Bacteriology ◽

10.1128/jb.00705-19 ◽

2020 ◽

Vol 202 (7) ◽

Author(s):

Prabhat Ranjan Singh ◽

Anil Kumar Vijjamarri ◽

Dibyendu Sarkar

Keyword(s):

Mycobacterium Tuberculosis ◽

Nitrogen Metabolism ◽

Electron Acceptor ◽

Latent Infection ◽

Critical Role ◽

Hypoxic Stress ◽

Content Type ◽

Metabolic Switching ◽

Virulence Regulator

ABSTRACT Mycobacterium tuberculosis retains the ability to establish an asymptomatic latent infection. A fundamental question in mycobacterial physiology is to understand the mechanisms involved in hypoxic stress, a critical player in persistence. Here, we show that the virulence regulator PhoP responds to hypoxia, the dormancy signal, and effectively integrates hypoxia with nitrogen metabolism. We also provide evidence to demonstrate that both under nitrogen limiting conditions and during hypoxia, phoP locus controls key genes involved in nitrogen metabolism. Consistently, under hypoxia a ΔphoP strain shows growth attenuation even with surplus nitrogen, the alternate electron acceptor, and complementation of the mutant restores bacterial growth. Together, our observations provide new biological insights into the role of PhoP in integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR. The results have significant implications on the mechanism of intracellular survival and growth of the tubercle bacilli under a hypoxic environment within the phagosome. IMPORTANCE M. tuberculosis retains the unique ability to establish an asymptomatic latent infection. To understand the mechanisms involved in hypoxic stress which play a critical role in persistence, we show that the virulence regulator PhoP is linked to hypoxia, the dormancy signal. In keeping with this, phoP was shown to play a major role in M. tuberculosis growth under hypoxia even in the presence of surplus nitrogen, the alternate electron acceptor. Our results showing regulation of hypoxia-responsive genes provide new biological insights into role of the virulence regulator in metabolic switching by sensing hypoxia and integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR.

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Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

Journal of Clinical Medicine ◽

10.3390/jcm9010143 ◽

2020 ◽

Vol 9 (1) ◽

pp. 143 ◽

Cited By ~ 6

Author(s):

Cinzia Fionda ◽

Helena Stabile ◽

Cristina Cerboni ◽

Alessandra Soriani ◽

Angela Gismondi ◽

...

Keyword(s):

Tumor Microenvironment ◽

Nk Cells ◽

Cancer Cells ◽

Nk Cell ◽

Critical Role ◽

Cell Activity ◽

Lymphoid Cells ◽

Receptor Expression ◽

Nk Cell Activity ◽

Group I

Transforming growth factor (TGF)-β is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-β is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-β rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-β can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-β-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-β in cancer. First, we will address how TGF-β impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-β may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic.

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Critical role of Rap1 in triggering the effects of microparticles from metabolic syndrome patients on vascular smooth muscle cell functions

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2018.02.165 ◽

2018 ◽

Vol 10 (2) ◽

pp. 252

Author(s):

L. Perdomo ◽

L. Vergori ◽

L. Duluc ◽

M. Chwastyniak ◽

M. Laudette ◽

...

Keyword(s):

Metabolic Syndrome ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Smooth Muscle Cell ◽

Critical Role ◽

Cell Functions

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Role of MSC in the Tumor Microenvironment

Cancers ◽

10.3390/cancers12082107 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2107 ◽

Cited By ~ 6

Author(s):

Ralf Hass

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Tumor Development ◽

Tumor Stroma ◽

Cell Types ◽

Cellular Interactions ◽

Cell Functions ◽

Metastatic Behavior ◽

Stem Cell Niches

The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous restructuring and growth in the tumor. A distinct organization of the tumor stroma also facilitates the formation of transient cancer stem cell niches, thereby contributing to progressive and dynamic tumor development. An important but heterogeneous mixture of cells that communicates among the cancer cells and the different tumor-associated cell types is represented by mesenchymal stroma-/stem-like cells (MSC). Following recruitment to tumor sites, MSC can change their functionalities, adapt to the tumor’s metabolism, undergo differentiation and synergize with cancer cells. Vice versa, cancer cells can alter therapeutic sensitivities and change metastatic behavior depending on the type and intensity of this MSC crosstalk. Thus, close cellular interactions between MSC and cancer cells can eventually promote cell fusion by forming new cancer hybrid cells. Consequently, newly acquired cancer cell functions or new hybrid cancer populations enlarge the plasticity of the tumor and counteract successful interventional strategies. The present review article highlights some important features of MSC within the tumor stroma.

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Metabolic switching of Mycobacterium tuberculosis during hypoxia is controlled by the virulence regulator PhoP

10.1101/845271 ◽

2019 ◽

Author(s):

Prabhat Ranjan Singh ◽

Vijjamarri Anil Kumar ◽

Dibyendu Sarkar

Keyword(s):

Mycobacterium Tuberculosis ◽

Nitrogen Metabolism ◽

Electron Acceptor ◽

Latent Infection ◽

Critical Role ◽

Hypoxic Stress ◽

Metabolic Switching ◽

Virulence Regulator ◽

Unique Ability

ABSTRACTMycobacterium tuberculosis (Mtb) retains the unique ability to establish an asymptomatic latent infection. A fundamental question in mycobacterial physiology is to understand the mechanisms involved in hypoxic stress, a critical player in persistence. Here, we show that the virulence regulator PhoP responds to hypoxia, the dormancy signal and effectively integrates hypoxia with nitrogen metabolism. We also provide evidence to demonstrate that both under nitrogen limiting conditions and during hypoxia, phoP locus controls key genes involved in nitrogen metabolism. Consistently, under hypoxia ΔphoP shows growth attenuation even with surplus nitrogen, the alternate electron acceptor, and complementation of the mutant restores bacterial growth. Together, our observations provide new biological insights into the role of PhoP in integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR. The results have significant implications on the mechanism of intracellular survival and growth of the tubercle bacilli under a hypoxic environment within the phagosome.ImportanceMtb retains the unique ability to establish an asymptomatic latent infection. To understand the mechanisms involved in hypoxic stress which plays a critical role in persistence, we show that the virulence regulator PhoP responds to hypoxia, the dormancy signal. In keeping with this, phoP was shown to play a major role in Mtb growth under hypoxia even in presence of surplus nitrogen, the alternate electron acceptor. Our results showing regulation of hypoxia-responsive genes provide new biological insights into role of the virulence regulator in metabolic switching by sensing hypoxia and integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR.

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Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20246342 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6342

Author(s):

Teizo Yoshimura ◽

Kaoru Nakamura ◽

Chunning Li ◽

Masayoshi Fujisawa ◽

Tsuyoshi Shiina ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Cancer Cell ◽

Lung Metastasis ◽

Cancer Progression ◽

Critical Role ◽

Gm Csf ◽

4T1 Cells

We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms.

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In Vitro Organotypic Systems to Model Tumor Microenvironment in Human Papillomavirus (HPV)-Related Cancers

Cancers ◽

10.3390/cancers12051150 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1150 ◽

Cited By ~ 3

Author(s):

Vincenza De Gregorio ◽

Francesco Urciuolo ◽

Paolo Antonio Netti ◽

Giorgia Imparato

Keyword(s):

Human Papillomavirus ◽

Tumor Microenvironment ◽

Critical Role ◽

Genetically Engineered ◽

Cancer Disease ◽

Raft Culture ◽

Squamous Epithelia

Despite the well-known role of chronic human papillomavirus (HPV) infections in causing tumors (i.e., all cervical cancers and other human malignancies from the mucosal squamous epithelia, including anogenital and oropharyngeal cavity), its persistence is not sufficient for cancer development. Other co-factors contribute to the carcinogenesis process. Recently, the critical role of the underlying stroma during the HPV life cycle and HPV-induced disease have been investigated. The tumor stroma is a key component of the tumor microenvironment (TME), which is a specialized entity. The TME is dynamic, interactive, and constantly changing—able to trigger, support, and drive tumor initiation, progression, and metastasis. In previous years, in vitro organotypic raft cultures and in vivo genetically engineered mouse models have provided researchers with important information on the interactions between HPVs and the epithelium. Further development for an in-depth understanding of the interaction between HPV-infected tissue and the surrounding microenvironment is strongly required. In this review, we critically describe the HPV-related cancers modeled in vitro from the simplified ‘raft culture’ to complex three-dimensional (3D) organotypic models, focusing on HPV-associated cervical cancer disease platforms. In addition, we review the latest knowledge in the field of in vitro culture systems of HPV-associated malignancies of other mucosal squamous epithelia (anogenital and oropharynx), as well as rare cutaneous non-melanoma associated cancer.

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