The Critical Role of Hypoxia in Tumor-Mediated Immunosuppression

Underestimated for a long time, the involvement of the microenvironment has been proven essential for a better understanding of the cancer development. In keeping with this, the tumor is not considered anymore as a mass of malignant cells, but rather as an organ composed of various malignant and nonmalignant cell populations interacting with each other to create the tumor microenvironment. The tumor immune contexture plays a critical role in shaping the tumor immune response, and it is now well supported that such an immune response is impacted by the hypoxic stress within the tumor microenvironment. Tumor hypoxia is closely linked to tumor progression, metastasis, treatment failure, and escape from immune surveillance. Thus, hypoxia seems to be a key factor involved in creating an immune-suppressive tumor by multiple overlapping mechanisms, including the impairment of the function of cytotoxic immune cells, increasing the immunosuppressive properties of immunosuppressive cells, and activating resistance mechanism in the tumor cells. In this chapter, we review some recent findings describing how hypoxic stress in the tumor microenvironment hijacks the antitumor immune response

Autophagy Regulation of the Tumor Immunity – An Old Machinery for a New Function

Cancer was initially thought to be just a disease of cells with deregulated gene expression. It may be more accurate to consider cancer as a disease of the microenvironment. Despite the remarkable and fairly rapid progress over the past two decades regarding the role of the microenvironment in cancer biology and treatment, our understanding of its actual contribution to cancer resistance is still poor and fragmented. Nevertheless, the microenvironment is now considered to be of critical importance during the initiation and progression of carcinogenesis since it is involved in shaping and remodeling stroma reactivity and in reprogramming phenotypic and functional plasticity. Therefore, the tumor microenvironment represents an important hallmark of cancer, and the challenge now is to better understand how the tumor microenvironment participates in the emergence of immune-resistant tumor cell variants, which appears to be the greatest impediment to successful immunotherapy. In this context, autophagy has recently emerged as a new player in regulating the antitumor immune response under hostile tumor microenvironment. In this review, we will summarize recent data describing how autophagy activation under hypoxic stress impairs the antitumor immune response. In addition, we will discuss how tumor manages to hide from the immune attack and either mounts a “counterattack” or develops resistance to immune cells. In particular, we will focus on the effect of hypoxia-induced autophagy in allowing tumor cells to outmaneuver an effective immune response and escape from immunosurveillance. It is our belief that autophagy may represent a conceptual realm for new immunotherapeutic strategies aiming to block immune escape and therefore providing rational approach to future tumor immunotherapy design

Ethnic and gender differences in applicants' decision-making processes: An application of the theory of reasoned action

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The human epidermal growth factor receptor (EGFR) gene in European patients with advanced colorectal cancer harbors infrequent mutations in its tyrosine kinase domain

ABSTRACT: BACKGROUND: The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptors, is a transmembrane tyrosine kinase (TK) activated by the binding of extracellular ligands of the EGF-family and involved in triggering the MAPK signaling pathway, which leads to cell proliferation. Mutations in the EGFR tyrosine kinase domain are frequent in non-small-cell lung cancer (NSCLC). However, to date, only very few, mainly non-European, studies have reported rare EGFR mutations in colorectal cancer (CRC). METHODS: We screened 236 clinical tumor samples from European patients with advanced CRC by direct DNA sequencing to detect potential, as yet unknown mutations, in the EGFR gene exons 18 to 21, mainly covering the EGFR TK catalytic domain. RESULTS: EGFR sequences showed somatic missense mutations in exons 18 and 20 at a frequency of 2.1% and 0.4% respectively. Somatic SNPs were also found in exons 20 and 21 at a frequency of about 3.1% and 0.4% respectively. Of these mutations, four have not yet been described elsewhere. CONCLUSIONS: These mutation frequencies are higher than in a similarly sized population characterized by Barber and colleagues, but still too low to account for a major role played by the EGFR gene in CRC.Peer reviewe

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Serine Protease PRSS23 Is Upregulated by Estrogen Receptor α and Associated with Proliferation of Breast Cancer Cells

Serine protease PRSS23 is a newly discovered protein that has been associated with tumor progression in various types of cancers. Interestingly, PRSS23 is coexpressed with estrogen receptor α (ERα), which is a prominent biomarker and therapeutic target for human breast cancer. Estrogen signaling through ERα is also known to affect cell proliferation, apoptosis, and survival, which promotes tumorigenesis by regulating the production of numerous downstream effector proteins