Dynamic altruistic cooperation within breast tumors.

BACKGROUND: Social behaviors such as altruism, where one self-sacrifices for collective benefits, critically influence an organism's survival and responses to the environment. Such behaviors are widely exemplified in nature but have been underexplored in cancer cells which are conventionally seen as selfish competitive players. This multidisciplinary study explores altruism and its mechanism in breast cancer cells and its contribution to chemoresistance. METHODS: MicroRNA profiling was performed on circulating tumor cells collected from the blood of treated breast cancer patients. Cancer cell lines ectopically expressing candidate miRNA were used in co-culture experiments and treated with docetaxel. Ecological parameters like relative survival and relative fitness were assessed using flow cytometry. Functional studies and characterization performed in vitro and in vivo include proliferation, iTRAQ-mass spectrometry, RNA sequencing, inhibition by small molecules and antibodies, siRNA knockdown, CRISPR/dCas9 inhibition and fluorescence imaging of promoter reporter-expressing cells. Mathematical modeling based on evolutionary game theory was performed to simulate spatial organization of cancer cells. RESULTS: Opposing cancer processes underlie altruism: an oncogenic process involving secretion of IGFBP2 and CCL28 by the altruists to induce survival benefits in neighboring cells under taxane exposure, and a self-sacrificial tumor suppressive process impeding proliferation of altruists via cell cycle arrest. Both processes are regulated concurrently in the altruists by miR-125b, via differential NF-κB signaling specifically through IKKß. Altruistic cells persist in the tumor despite their self-sacrifice, as they can regenerate epigenetically from non-altruists via a KLF2/PCAF-mediated mechanism. The altruists maintain a sparse spatial organization by inhibiting surrounding cells from adopting the altruistic fate via a lateral inhibition mechanism involving a GAB1-PI3K-AKT-miR-125b signaling circuit. CONCLUSIONS: Our data reveal molecular mechanisms underlying manifestation, persistence and spatial spread of cancer cell altruism. A minor population behave altruistically at a cost to itself producing a collective benefit for the tumor, suggesting tumors to be dynamic social systems governed by the same rules of cooperation in social organisms. Understanding cancer cell altruism may lead to more holistic models of tumor evolution and drug response, as well as therapeutic paradigms that account for social interactions. Cancer cells constitute tractable experimental models for fields beyond oncology, like evolutionary ecology and game theory.

Sensory nerves mediate spontaneous behaviors in addition to inflammation in a murine model of psoriasis.

Psoriasis is characterized by keratinocyte hyperproliferation, erythema, as well as a form of pruritus, involving cutaneous discomfort. There is evidence from both clinical and murine models of psoriasis that chemical or surgical depletion of small-diameter sensory nerves/nociceptors benefits the condition, but the mechanisms are unclear. Hence, we aimed to understand the involvement of sensory nerve mediators with a murine model of psoriasis and associated spontaneous behaviors, indicative of cutaneous discomfort. We have established an Aldara model of psoriasis in mice and chemically depleted the small-diameter nociceptors in a selective manner. The spontaneous behaviors, in addition to the erythema and skin pathology, were markedly improved. Attenuated inflammation was associated with reduced dermal macrophage influx and production of reactive oxygen/nitrogen species (peroxynitrite and protein nitrosylation). Subsequently, this directly influenced observed behavioral responses. However, the blockade of common sensory neurogenic mechanisms for transient receptor potential (TRP)V1, TRPA1, and neuropeptides (substance P and calcitonin gene-related peptide) using genetic and pharmacological approaches inhibited the behaviors but not the inflammation. Thus, a critical role of the established sensory TRP-neuropeptide pathway in influencing cutaneous discomfort is revealed, indicating the therapeutic potential of agents that block that pathway. The ongoing inflammation is mediated by a distinct sensory pathway involving macrophage activation.-Kodji, X., Arkless, K. L., Kee, Z., Cleary, S. J., Aubdool, A. A., Evans, E., Caton, P., Pitchford, S. C., Brain, S. D. Sensory nerves mediate spontaneous behaviors in addition to inflammation in a murine model of psoriasis.

Androgen-dependent tissue factor pathway inhibitor regulating protein: a review of its peripheral actions and association with cardiometabolic diseases.

The first genome-wide association study on coronary artery disease (CAD) in the Han Chinese population identified C6orf105 as a susceptibility gene. The C6orf105 gene was later found to encode for a protein that regulates tissue factor pathway inhibitor (TFPI) expression in endothelial cells in an androgen-dependent manner, and the novel protein was thus termed androgen-dependent TFPI-regulating protein (ADTRP). Since the identification of ADTRP, there have been several studies associating genetic variants on the ADTRP gene with CAD risk, as well as research providing mechanistic insights on this novel protein and its functional role. ADTRP is a membrane protein, whose expression is upregulated by androgen, GATA-binding protein 2, oxidized low-density lipoprotein, peroxisome proliferator-activated receptors, and low-density lipoprotein receptors. ADTRP regulates multiple downstream targets involved in coagulation, inflammation, endothelial function, and vascular integrity. In addition, ADTRP functions as a fatty acid esters of hydroxy fatty acid (FAHFA)-specific hydrolase that is involved in energy metabolism. Current evidence suggests that ADTRP may play a role in the pathogenesis of atherosclerosis, CAD, obesity, and metabolic disorders. This review summarizes the current literature on ADTRP, with a focus on the peripheral actions of ADTRP, including expression, genetic variations, signaling pathways, and function. The evidence linking ADTRP and cardiometabolic diseases will also be discussed.

Evidence That a TRPA1-Mediated Murine Model of Temporomandibular Joint Pain Involves NLRP3 Inflammasome Activation.

This study investigates the role of transient receptor potential ankyrin 1 (TRPA1) in murine temporomandibular joint (TMJ) inflammatory hyperalgesia and the influence of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Two distinct murine models of TMJ pain and inflammation (zymosan and CFA) were established. Spontaneous pain-like behaviours were observed as unilateral front paw cheek wipes. Ipsilateral cheek blood flow was used as a measure of ongoing inflammation, which, to our knowledge, is a novel approach to assessing real-time inflammation in the TMJ. Joint tissue and trigeminal ganglia were collected for ex vivo investigation. Both zymosan and CFA induced a time-dependent increase in hyperalgesia and inflammation biomarkers. Zymosan induced a significant effect after 4 h, correlating with a significantly increased IL-1ß protein expression. CFA (50 µg) induced a more sustained response. The TRPA1 receptor antagonist A967079 significantly inhibited hyper-nociception. The NLRP3 inhibitor MCC950 similarly inhibited hyper-nociception, also attenuating inflammatory markers. In the trigeminal ganglia, CFA-induced CGRP expression showed trends of inhibition by A967079, whilst lba1 immunofluorescence was significantly inhibited by A967079 and MCC950, where the effect of TRPA1 inhibition lasted up to 14 days. Our results show that stimulation of TRPA1 is key to the TMJ pain. However, the inflammasome inhibitor exhibited similar properties in attenuating these pain-like behaviours, in addition to some inflammatory markers. This indicates that in addition to the therapeutic targeting of TRPA1, NLRP3 inhibition may provide a novel therapeutic strategy for TMJ inflammation and pain.

The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects.

Calcitonin gene-related peptide (CGRP) is a highly potent vasoactive peptide released from sensory nerves, which is now proposed to have protective effects in several cardiovascular diseases. The major α-form is produced from alternate splicing and processing of the calcitonin gene. The CGRP receptor is a complex composed of calcitonin like receptor (CLR) and a single transmembrane protein, RAMP1. CGRP is a potent vasodilator and proposed to have protective effects in several cardiovascular diseases. CGRP has a proven role in migraine and selective antagonists and antibodies are now reaching the clinic for treatment of migraine. These clinical trials with antagonists and antibodies indicate that CGRP does not play an obvious role in the physiological control of human blood pressure. This review discusses the vasodilator and hypotensive effects of CGRP and the role of CGRP in mediating cardioprotective effects in various cardiovascular models and disorders. In models of hypertension, CGRP protects against the onset and progression of hypertensive states by potentially counteracting against the pro-hypertensive systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic system. With regards to its cardioprotective effects in conditions such as heart failure and ischaemia, CGRP-containing nerves innervate throughout cardiac tissue and the vasculature, where evidence shows this peptide alleviates various aspects of their pathophysiology, including cardiac hypertrophy, reperfusion injury, cardiac inflammation, and apoptosis. Hence, CGRP has been suggested as a cardioprotective, endogenous mediator released under stress to help preserve cardiovascular function. With the recent developments of various CGRP-targeted pharmacotherapies, in the form of CGRP antibodies/antagonists as well as a CGRP analog, this review provides a summary and a discussion of the most recent basic science and clinical findings, initiating a discussion on the future of CGRP as a novel target in various cardiovascular diseases.

Longitudinal monitoring reveals dynamic changes in circulating tumor cells (CTCs) and CTC-associated miRNAs in response to chemotherapy in metastatic colorectal cancer patients.

We evaluated the changes in CTC count and CTC-associated miRNAs during the course of chemotherapy in patients with metastatic colorectal cancer. Blood samples were collected from 9 metastatic colorectal cancer patients prior to chemotherapy and at every other chemotherapy session during the course of treatment. CTCs were isolated and enumerated using a size-exclusion method (CellSievo, Singapore). CTC-associated miRNAs were isolated using a paper-based, partitioning method, and analyzed using reverse transcription quantitative real-time PCR (MiRXES, Singapore). CTC count trends generally correlated with disease progression defined by radiological measurements and trends in carcinoembryonic antigen (CEA) levels; hence CTC counts may be useful in cases where CEA is not elevated. CTC-associated miRNAs identified were miR-15b, miR-16, miR-19a, miR-21, miR-25, miR-30d, miR-126, miR-185, miR-221, miR-222, and miR-324-5p. The expression of CTC-associated miRNAs did not appear to correlate with CTC count and exhibited inter-individual heterogeneity. This pilot study suggests that analysis of CTC changes during the course of treatment may be useful in monitoring response to therapy in metastatic colorectal cancer.