Macrophages are a major component of the tumor microenvironment and orchestrate various aspects of immunity. Within tumors, macrophages can reversibly alter their endotype in response to ...environmental cues, including hypoxia and stimuli derived from other immune cells, as well as the extracellular matrix. Depending on their activation status, macrophages can exert dual influences on tumorigenesis by either antagonizing the cytotoxic activity immune cells or by enhancing antitumor responses. In most solid cancers, increased infiltration with tumor-associated macrophages (TAMs) has long been associated with poor patient prognosis, highlighting their value as potential diagnostic and prognostic biomarkers in cancer. A number of macrophage-centered approaches to anticancer therapy have been investigated, and include strategies to block their tumor-promoting activities or exploit their antitumor effector functions. Integrating therapeutic strategies to target TAMs to complement conventional therapies has yielded promising results in preclinical trials and warrants further investigation to determine its translational benefit in human cancer patients. In this review, we discuss the molecular mechanisms underlying the pro-tumorigenic programming of macrophages and provide a comprehensive update of macrophage-targeted therapies for the treatment of solid cancers.
We present a systematic approach to reduce the dimensionality of a complex molecular system. Starting with a data set of molecular coordinates (obtained from experiment or simulation) and an ...associated set of metastable conformational states (obtained from clustering the data), a supervised machine learning model is trained to assign unknown molecular structures to the set of metastable states. In this way, the model learns to determine the features of the molecular coordinates that are most important to discriminate the states. Using a new algorithm that exploits this feature importance via an iterative exclusion principle, we identify the essential internal coordinates (such as specific interatomic distances or dihedral angles) of the system, which are shown to represent versatile reaction coordinates that account for the dynamics of the slow degrees of freedom and explain the mechanism of the underlying processes. Moreover, these coordinates give rise to a free energy landscape that may reveal previously hidden intermediate states of the system.
Abstract Intercellular communication between tumor cells, immune cells and the stroma characterises the tumor microenvironment, which is instrumental for establishing the ecological niche that ...fosters tumor growth and metastasis. While tumor cell intrinsic STAT3 signaling provides a crucial axis to support cell proliferation and survival, it also regulates many activities of the non-transformed cells that collectively make up the tumor microenvironment. Accordingly, excessive activation of STAT3 is a hallmark of many malignancies, and often occurs in response to cytokines of the IL-6 and IL-10 families. However, tumor extrinsic STAT3 signaling also regulates the effector function of tumor-associated immune and stromal cells, which support the growth of tumors by suppressing the host’s anti-tumor immune response. Given that STAT3 mediates tumorigenic effects in many cell types, the molecular players of STAT3 signaling and its upstream JAK kinases provide viable therapeutic targets for the treatment of cancer. Here we provide an update on novel insights into the role of STAT3 in immune suppression and describe current therapeutic strategies that target the JAK/STAT3 signaling axis for the treatment of malignancies.
Review discusses newly emerging role for IL‐11 in inflammation‐associated cancers of the gastrointestinal tract.
IL‐11, a member of the IL‐6 family of cytokines, exerts pleiotropic activities by ...stimulating hemopoiesis and thrombopoiesis, regulating macrophage differentiation, and conferring mucosal protection in the intestine. These effects are mediated by a multimeric complex comprising the ligand‐binding IL‐11Rα and the ubiquitously expressed gp130R β‐subunit, which together, trigger intracellular signaling and engagement of Stat3. In turn, activated Stat3 promotes cell survival and proliferation as well as immune responses associated with inflammatory diseases and tumor progression. IL‐6 and IL‐11 compete for interaction with gp130, resulting in tissue‐specific functions depending on the expression patterns of their respective α‐subunit receptors. Although traditionally, IL‐6 has been associated with aberrant Stat3 activation and associated pathologies, here, we discuss newly emerging roles for IL‐11 in linking inflammation to cancer progression. We propose that in light of the recurrence of persistent STAT3 activation and elevated IL‐11 expression in inflammation‐associated gastrointestinal cancers in humans, inhibition of Stat3 or pharmacologically, more amenable upstream molecules such as IL‐11 may represent novel, therapeutic targets.
To interpret molecular dynamics simulations of complex systems, systematic dimensionality reduction methods such as principal component analysis (PCA) represent a well-established and popular ...approach. Apart from Cartesian coordinates, internal coordinates, e.g., backbone dihedral angles or various kinds of distances, may be used as input data in a PCA. Adopting two well-known model problems, folding of villin headpiece and the functional dynamics of BPTI, a systematic study of PCA using distance-based measures is presented which employs distances between Cα-atoms as well as distances between inter-residue contacts including side chains. While this approach seems prohibitive for larger systems due to the quadratic scaling of the number of distances with the size of the molecule, it is shown that it is sufficient (and sometimes even better) to include only relatively few selected distances in the analysis. The quality of the PCA is assessed by considering the resolution of the resulting free energy landscape (to identify metastable conformational states and barriers) and the decay behavior of the corresponding autocorrelation functions (to test the time scale separation of the PCA). By comparing results obtained with distance-based, dihedral angle, and Cartesian coordinates, the study shows that the choice of input variables may drastically influence the outcome of a PCA.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of less than 10%. Macrophages are one of the earliest infiltrating cells in the pancreatic tumor ...microenvironment, and are associated with an increased risk of disease progression, recurrence, metastasis, and shorter overall survival. Pre-clinical studies have demonstrated an unequivocal role of macrophages in PDAC by contributing to chronic inflammation, cancer cell stemness, desmoplasia, immune suppression, angiogenesis, invasion, metastasis, and drug resistance. Several macrophage-targeting therapies have also been investigated in pre-clinical models, and include macrophage depletion, inhibiting macrophage recruitment, and macrophage reprogramming. However, the effectiveness of these drugs in pre-clinical models has not always translated into clinical trials. In this review, we discuss the molecular mechanisms that underpin macrophage heterogeneity within the pancreatic tumor microenvironment, and examine the contribution of macrophages at various stages of PDAC progression. We also provide a comprehensive update of macrophage-targeting therapies that are currently undergoing clinical evaluation, and discuss clinical challenges associated with these treatment modalities in human PDAC patients.
Emerging evidence suggests that cytokines produced by inflammatory cells act as rheostats to link the degree of wounding and local inflammation to epithelial cell survival, proliferation, and ...metabolism that collectively underpin the repair response. Among these cytokines, the GP130 family, which encompasses, among others, IL6 and IL11, plays a major role in orchestrating these complex processes through the activation of the latent signal transducer and activator of transcription 3 (STAT3) in the epithelium. However, many of the molecular mechanisms that govern and ensure effective epithelial wound healing and regeneration renewal also promote tumorigenesis and the progression of established cancers. Accordingly, GP130 cytokines endow the inflammatory tumor microenvironment with a capacity to promote "cancer hallmark capabilities" of the malignant epithelium, while simultaneously suppressing the antitumor response of innate and adaptive immune cells. Here, we review some recent insights derived from genetic and therapeutic inhibition of the IL6/IL11-GP130-STAT3 signaling cascade in the context of preclinical mouse models of cancer, which are likely to have implications to other solid malignancies.
Inflammation is an important environmental factor that promotes tumourigenesis and the progression of established cancerous lesions, and recent studies have started to dissect the mechanisms linking ...the two pathologies. These inflammatory and infectious conditions trigger immune and stromal cell release of soluble mediators which facilitate survival and proliferation of tumour cells in a paracrine manner. In addition, (epi-)genetic mutations affecting oncogenes, tumour-suppressor genes, chromosomal rearrangements and amplifications trigger the release of inflammatory mediators within the tumour microenvironment to promote neoplastic growth in an autocrine manner. These two pathways converge in tumour cells and result in activation of the latent signal transducer and activator of transcription 3 (Stat3) which mediates a transcriptional response favouring survival, proliferation and angiogenesis. The abundance of cytokines that activate Stat3 within the tumour microenvironment, which comprises of members of the interleukin (IL) IL6, IL10 and IL17/23 families, underpins a signaling network that simultaneously promotes the growth of neoplastic epithelium, fuels inflammation and suppresses the host's anti-tumour immune response. Accordingly, aberrant and persistent Stat3 activation is a frequent observation in human cancers of epithelial origin and is often associated with poor outcome.Here we summarize insights gained from mice harbouring mutations in components of the Stat3 signaling cascade and in particular of gp130, the shared receptor for the IL6 family of cytokines. We focus on the various feed-back and feed-forward loops in which Stat3 provides the signaling node in cells of the tumour and its microenvironment thereby functionally linking excessive inflammation to neoplastic growth. Although these observations are particularly pertinent to gastrointestinal tumours, we suggest that the tumour's addiction to persistent Stat3 activation is likely to also impact on other epithelial cell-derived cancers. These insights provide clues to the judicious interference of the gp130/Stat3 signaling cascade in therapeutically targeting cancer.
We report linewidth and proton
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Highlights • The IL-11/GP130/JAK/STAT3 signaling axis is rate-limiting for the progression of gastrointestinal tumors. • Elevated IL-11 expression is associated with poor breast cancer patient ...prognosis. • Through STAT3, IL-11 endows “Hallmarks of Cancer” activities, including survival, proliferation, invasion, angiogenesis and metastasis. • IL-11 and IL-6 influence breast cancer stem cell dynamics and tumor heterogeneity. • Various strategies to interfere with binding of IL-11 to its cognate IL-11Rα receptor are being developed.
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