Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.

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Microenvironmental regulation of metastasis

The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.

/pdf/psychological-stress-and-the-human-immune-system-a-meta-3lp53rp4yz.pdf

Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry

The clonal selection principle is used to explain the basic features of an adaptive immune response to an antigenic stimulus. It establishes the idea that only those cells that recognize the antigens (Ag's) are selected to proliferate. The selected cells are subject to an affinity maturation process, which improves their affinity to the selective Ag's. This paper proposes a computational implementation of the clonal selection principle that explicitly takes into account the affinity maturation of the immune response. The general algorithm, named CLONALG, is derived primarily to perform machine learning and pattern recognition tasks, and then it is adapted to solve optimization problems, emphasizing multimodal and combinatorial optimization. Two versions of the algorithm are derived, their computational cost per iteration is presented, and a sensitivity analysis in relation to the user-defined parameters is given. CLONALG is also contrasted with evolutionary algorithms. Several benchmark problems are considered to evaluate the performance of CLONALG and it is also compared to a niching method for multimodal function optimization.

/pdf/learning-and-optimization-using-the-clonal-selection-fjnwsvdguv.pdf

Learning and optimization using the clonal selection principle

Here, we demonstrate a previously unknown function for the 70-kDa heat-shock protein (HSP70) as a cytokine. HSP70 bound with high affinity to the plasma membrane, elicited a rapid intracellular calcium flux, activated nuclear factor (NF)-kappaB and upregulated the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in human monocytes. Furthermore, two different signal transduction pathways were activated by exogenous HSP70: one dependent on CD14 and intracellular calcium, which resulted in increased IL-1beta, IL-6 and TNF-alpha; and the other independent of CD14 but dependent on intracellular calcium, which resulted in an increase in TNF-alpha but not IL-1beta or IL-6. These findings indicate that CD14 is a co-receptor for HSP70-mediated signaling in human monocytes and are indicative of an previously unrecognized function for HSP70 as an extracellular protein with regulatory effects on human monocytes, having a dual role as chaperone and cytokine.

HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine.

CD40-CD154-mediated contact-dependent signals between B and T cells are required for the generation of thymus dependent (TD) humoral immune responses. CD40-CD154 interactions are however also important in many other cell systems. CD40 is expressed by a large variety of cell types other than B cells, and these include dendritic cells, follicular dendritic cells, monocytes, macrophages, mast cells, fibroblasts, and endothelial cells. CD40- and CD154-knockout mice and antibodies to CD40 and CD154 have helped to elucidate the role of the CD40-CD154 system in immune responses. Recently published studies indicate that CD40-CD154 interactions can influence T cell priming and T cell-mediated effector functions; they can also upregulate costimulatory molecules and activate macrophages, NK cells, and endothelia as well as participate in organ-specific autoimmune disease, graft rejection, and even atherosclerosis. This review focuses on the role of the CD40-CD154 system in the regulation of many newly discovered functions important in inflammation and cell-mediated immunity.

Charles A. Janeway

Papers

Immunobiology : the immune system in health and disease [Janeway, 2001]