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Defects in microarchitected materials exhibit a dual nature, capable of both unlocking innovative functionalities and degrading their performance. Specifically, while intentional defects are strategically introduced to customize and enhance mechanical responses, inadvertent defects stemming from manufacturing errors can disrupt the symmetries and intricate interactions within these materials. In this study, we demonstrate a nondestructive optical imaging technique that can precisely locate defects inside microscale metamaterials, as well as provide detailed insights on the specific type of defect.
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Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations. Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.
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Neoplasias de la Mama , Glutamato-Cisteína Ligasa , Glutatión , Homeostasis , Neoplasias Hepáticas , Oxidación-Reducción , Especies Reactivas de Oxígeno , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Humanos , Glutatión/metabolismo , Animales , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/genética , Ratones , Línea Celular Tumoral , Glutamato-Cisteína Ligasa/metabolismo , Glutamato-Cisteína Ligasa/genética , Glucólisis , Metástasis de la Neoplasia , Regulación Neoplásica de la Expresión Génica , Microambiente TumoralRESUMEN
OBJECTIVE: Obstructive sleep apnea (OSA) is a common risk factor for stroke, and dysphagia and pneumonia are both well-known complications of stroke. The development of these conditions is related to the oropharyngeal structures. We investigated whether specific structural features of the tongue may lead to the development of these complications. METHODS: Patients with ischemic stroke who required admission and community-dwelling elderly controls were enrolled. The participants underwent tongue measurements by received hand-held ultrasound, and received questionnaires to evaluate sleep quality and daytime sleepiness. The patient group also underwent objective sleep measurement by actigraphy and the 3-Step Swallowing Test (3-SSS). Sleep parameters and outcomes were analyzed. RESULTS: Patient with ischemic stroke had significantly thicker tongue than controls (6.53 cm v. 6.05 cm, p = 0.002). Multiple logistic regression analysis revealed that the anatomical parameters of the tongue in patients with stroke were significantly correlated with parameters of OSA, and the thickness of the tongue was positively correlated with the development of OSA (p = 0.024) and pneumonia (p = 0.048). CONCLUSIONS: A thicker-than average tongue may be a risk factor for OSA and pneumonia in patient with stroke. Hand-held ultrasound can be used to identify these anatomical features. Further studies are warranted to clarify the role of the tongue in these post-stroke complications.
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Trastornos de Deglución , Accidente Cerebrovascular Isquémico , Neumonía , Apnea Obstructiva del Sueño , Accidente Cerebrovascular , Humanos , Anciano , Trastornos de Deglución/etiología , Trastornos de Deglución/complicaciones , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/diagnóstico por imagen , Lengua/diagnóstico por imagen , Neumonía/etiología , Neumonía/complicacionesRESUMEN
Recent advances in two-photon polymerization fabrication processes are paving the way to creating macroscopic metamaterials with microscale architectures, which exhibit mechanical properties superior to their bulk material counterparts. These metamaterials typically feature lightweight, complex patterns such as lattice or minimal surface structures. Conventional tools for investigating these microscale structures, such as scanning electron microscopy, cannot easily probe the internal features of these structures, which are critical for a comprehensive assessment of their mechanical behavior. In turn, we demonstrate an optical confocal microscopy-based approach that allows for high-resolution optical imaging of internal deformations and fracture processes in microscale metamaterials under mechanical load. We validate this technique by investigating an exemplary metamaterial lattice structure of 80 × 80 × 80 µm3 in size. This technique can be extended to other metamaterial systems and holds significant promise to enhance our understanding of their real-world performance under loading conditions.
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Transmembrane glycoprotein NMB (GPNMB) is a prognostic marker of poor outcome in patients with triple-negative breast cancer (TNBC). Glembatumumab Vedotin, an antibody drug conjugate targeting GPNMB, exhibits variable efficacy against GPNMB-positive metastatic TNBC as a single agent. We show that GPNMB levels increase in response to standard-of-care and experimental therapies for multiple breast cancer subtypes. While these therapeutic stressors induce GPNMB expression through differential engagement of the MiTF family of transcription factors, not all are capable of increasing GPNMB cell-surface localization required for Glembatumumab Vedotin inhibition. Using a FACS-based genetic screen, we discovered that suppression of heat shock protein 90 (HSP90) concomitantly increases GPNMB expression and cell-surface localization. Mechanistically, HSP90 inhibition resulted in lysosomal dispersion towards the cell periphery and fusion with the plasma membrane, which delivers GPNMB to the cell surface. Finally, treatment with HSP90 inhibitors sensitizes breast cancers to Glembatumumab Vedotin in vivo, suggesting that combination of HSP90 inhibitors and Glembatumumab Vedotin may be a viable treatment strategy for patients with metastatic TNBC.
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Antineoplásicos , Inmunoconjugados , Neoplasias de la Mama Triple Negativas , Anticuerpos Monoclonales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Membrana Celular/metabolismo , Humanos , Inmunoconjugados/efectos adversos , Lisosomas/metabolismo , Glicoproteínas de Membrana/genética , Factores de Transcripción , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Neutrophils are the first leukocytes recruited to sites of inflammation, where they execute anti-microbial functions to eliminate infectious agents. These functions include phagocytosis, release of reactive oxygen species and the formation of neutrophil extracellular traps via NETosis. Neutrophils are receiving increasing attention in the context of cancer, where these same neutrophil-associated functions are also important for modulating tumor growth and metastatic progression. Neutrophils are phenotypically heterogeneous and, depending on the context, exert anti- or pro-tumorigenic functions. Increasing evidence also suggests an important role of neutrophils and their involvement in promoting multiple steps of the metastatic cascade. The steps include: (1) local invasion and intravasation of cancer cells into circulation, (2) survival of cancer cells in the bloodstream and extravasation at a distant site, (3) early cancer cell seeding/survival, and (4) progressive growth of cancer cells to form macroscopic metastases. Although neutrophil functions designed to eliminate infectious agents can also eliminate tumor cells, their dysregulation can promote tumor growth and enable metastasis at multiple steps along the metastatic cascade. In this review, we will provide an overview of the current advances in neutrophil biology in the context of cancer. We also discuss the emerging field of immunometabolism, in which the rewiring of alternative metabolic pathways within neutrophils can impact their pro-tumorigenic/pro-metastatic functions.
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Invasividad Neoplásica/inmunología , Neoplasias/inmunología , Neoplasias/patología , Neutrófilos/inmunología , Animales , Humanos , FenotipoRESUMEN
Neutrophils represent the immune system's first line of defense and are rapidly recruited into inflamed tissue. In cancer associated inflammation, phenotypic heterogeneity has been ascribed to this cell type, whereby neutrophils can manifest anti- or pro-metastatic functions depending on the cellular/micro-environmental context. Here, we demonstrate that pro-metastatic immature low-density neutrophils (iLDNs) more efficiently accumulate in the livers of mice bearing metastatic lesions compared with anti-metastatic mature high-density neutrophils (HDNs). Transcriptomic analyses reveal enrichment of a migration signature in iLDNs relative to HDNs. We find that conditioned media derived from liver-metastatic breast cancer cells, but not lung-metastatic variants, specifically induces chemotaxis of iLDNs and not HDNs. Chemotactic responses are due to increased surface expression of C3aR in iLDNs relative to HDNs. In addition, we detect elevated secretion of cancer-cell derived C3a from liver-metastatic versus lung-metastatic breast cancer cells. Perturbation of C3a/C3aR signaling axis with either a small molecule inhibitor, SB290157, or reducing the levels of secreted C3a from liver-metastatic breast cancer cells by short hairpin RNAs, can abrogate the chemotactic response of iLDNs both in vitro and in vivo, respectively. Together, these data reveal novel mechanisms through which iLDNs prefentially accumulate in liver tissue harboring metastases in response to tumor-derived C3a secreted from the liver-aggressive 4T1 breast cancer cells.
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Complemento C3a/inmunología , Neoplasias Hepáticas/inmunología , Neutrófilos/inmunología , Animales , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular , Medios de Cultivo Condicionados , Femenino , Neoplasias Hepáticas/secundario , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Receptores de Complemento/agonistas , Receptores de Complemento/metabolismoRESUMEN
Recent evidence demonstrates that novel protein-coding genes can arise de novo from non-genic loci. This evolutionary innovation is thought to be facilitated by the pervasive translation of non-genic transcripts, which exposes a reservoir of variable polypeptides to natural selection. Here, we systematically characterize how these de novo emerging coding sequences impact fitness in budding yeast. Disruption of emerging sequences is generally inconsequential for fitness in the laboratory and in natural populations. Overexpression of emerging sequences, however, is enriched in adaptive fitness effects compared to overexpression of established genes. We find that adaptive emerging sequences tend to encode putative transmembrane domains, and that thymine-rich intergenic regions harbor a widespread potential to produce transmembrane domains. These findings, together with in-depth examination of the de novo emerging YBR196C-A locus, suggest a novel evolutionary model whereby adaptive transmembrane polypeptides emerge de novo from thymine-rich non-genic regions and subsequently accumulate changes molded by natural selection.
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Evolución Molecular , Proteínas de la Membrana/genética , Proteínas de Saccharomyces cerevisiae/genética , Factores Asociados con la Proteína de Unión a TATA/genética , Timina , Factor de Transcripción TFIID/genética , Adaptación Biológica/genética , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Regulación Fúngica de la Expresión Génica , Aptitud Genética , Membranas Intracelulares/metabolismo , Proteínas de la Membrana/química , Sistemas de Lectura Abierta , Dominios Proteicos/genética , Saccharomyces cerevisiae/genéticaRESUMEN
BACKGROUND: The p66ShcA redox protein is the longest isoform of the Shc1 gene and is variably expressed in breast cancers. In response to a variety of stress stimuli, p66ShcA becomes phosphorylated on serine 36, which allows it to translocate from the cytoplasm to the mitochondria where it stimulates the formation of reactive oxygen species (ROS). Conflicting studies suggest both pro- and anti-tumorigenic functions for p66ShcA, which prompted us to examine the contribution of tumor cell-intrinsic functions of p66ShcA during breast cancer metastasis. METHODS: We tested whether p66ShcA impacts the lung-metastatic ability of breast cancer cells. Breast cancer cells characteristic of the ErbB2+/luminal (NIC) or basal (4T1) subtypes were engineered to overexpress p66ShcA. In addition, lung-metastatic 4T1 variants (4T1-537) were engineered to lack endogenous p66ShcA via Crispr/Cas9 genomic editing. p66ShcA null cells were then reconstituted with wild-type p66ShcA or a mutant (S36A) that cannot translocate to the mitochondria, thereby lacking the ability to stimulate mitochondrial-dependent ROS production. These cells were tested for their ability to form spontaneous metastases from the primary site or seed and colonize the lung in experimental (tail vein) metastasis assays. These cells were further characterized with respect to their migration rates, focal adhesion dynamics, and resistance to anoikis in vitro. Finally, their ability to survive in circulation and seed the lungs of mice was assessed in vivo. RESULTS: We show that p66ShcA increases the lung-metastatic potential of breast cancer cells by augmenting their ability to navigate each stage of the metastatic cascade. A non-phosphorylatable p66ShcA-S36A mutant, which cannot translocate to the mitochondria, still potentiated breast cancer cell migration, lung colonization, and growth of secondary lung metastases. However, breast cancer cell survival in the circulation uniquely required an intact p66ShcA S36 phosphorylation site. CONCLUSION: This study provides the first evidence that both mitochondrial and non-mitochondrial p66ShcA pools collaborate in breast cancer cells to promote their maximal metastatic fitness.
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Neoplasias de la Mama/patología , Neoplasias Pulmonares/secundario , Mitocondrias/patología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Mitocondrias/metabolismo , FosforilaciónRESUMEN
Neutrophils are phenotypically heterogeneous and exert either anti- or pro-metastatic functions. We show that cancer-cell-derived G-CSF is necessary, but not sufficient, to mobilize immature low-density neutrophils (iLDNs) that promote liver metastasis. In contrast, mature high-density neutrophils inhibit the formation of liver metastases. Transcriptomic and metabolomic analyses of high- and low-density neutrophils reveal engagement of numerous metabolic pathways specifically in low-density neutrophils. iLDNs exhibit enhanced global bioenergetic capacity, through their ability to engage mitochondrial-dependent ATP production, and remain capable of executing pro-metastatic neutrophil functions, including NETosis, under nutrient-deprived conditions. We demonstrate that NETosis is an important neutrophil function that promotes breast cancer liver metastasis. iLDNs rely on the catabolism of glutamate and proline to support mitochondrial-dependent metabolism in the absence of glucose, which enables sustained NETosis. These data reveal that distinct pro-metastatic neutrophil populations exhibit a high degree of metabolic flexibility, which facilitates the formation of liver metastases.
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Neoplasias Hepáticas/metabolismo , Neoplasias Mamarias Experimentales/metabolismo , Neutrófilos/metabolismo , Animales , Línea Celular Tumoral , Femenino , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Neutrófilos/patologíaRESUMEN
The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E). We and others have shown that eIF4E availability and phosphorylation promote metastasis in mouse models of breast cancer by selectively augmenting the translation of mRNAs involved in invasion and metastasis. However, the impact of translational control in cell types within the tumor microenvironment (TME) is unknown. Here, we demonstrate that regulatory events affecting translation in cells of the TME impact cancer progression. Mice bearing a mutation in the phosphorylation site of eIF4E (S209A) in cells comprising the TME are resistant to the formation of lung metastases in a syngeneic mammary tumor model. This is associated with reduced survival of prometastatic neutrophils due to decreased expression of the antiapoptotic proteins BCL2 and MCL1. Furthermore, we demonstrate that pharmacological inhibition of eIF4E phosphorylation prevents metastatic progression in vivo, supporting the development of phosphorylation inhibitors for clinical use.
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Neoplasias de la Mama/patología , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Neutrófilos/metabolismo , Biosíntesis de Proteínas , Microambiente Tumoral , Secuencias de Aminoácidos , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Factor 4E Eucariótico de Iniciación/química , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Metástasis de la Neoplasia , Fosforilación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
In previous studies we found that macrophages (MФs) from SH2-containing inositol-5'-phosphatase (SHIP) deficient mice are M2 polarized while their wild type (WT) counterparts are M1 polarized and that this difference in MФ phenotype can be recapitulated during in vitro derivation from bone marrow if mouse plasma (MP), but not fetal calf serum, is added to standard M-CSF-containing cultures. In the current study we investigated the mechanism by which MP skews SHIP-/- but not +/+ MФs to an M2 phenotype. Our results suggest that SHIP-/- basophils constitutively secrete higher levels of IL-4 than SHIP+/+ basophils and this higher level of IL-4 is sufficient to skew both SHIP+/+ and SHIP-/- MФs to an M2 phenotype, but only when MP is present to increase the sensitivity of the MФs to this level of IL-4. MP increases the IL-4 sensitivity of both SHIP+/+ and -/- MФs not by increasing cell surface IL-4 or CD36 receptor levels, but by triggering the activation of Erk and Akt and the production of ROS, all of which play a critical role in sensitizing MФs to IL-4-induced M2 skewing. Studies to identify the factor(s) in MP responsible for promoting IL-4-induced M2 skewing suggests that all-trans retinoic acid (ATRA), TGFß and prostaglandin E2 (PGE2) all play a role. Taken together, these results indicate that basophil-secreted IL-4 plays an essential role in M2 skewing and that ATRA, TGFß and PGE2 within MP collaborate to dramatically promote M2 skewing by acting directly on MФs to increase their sensitivity to IL-4.
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Basófilos/metabolismo , Dinoprostona/farmacología , Interleucina-4/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/metabolismo , Plasma/química , Factor de Crecimiento Transformador beta/farmacología , Tretinoina/farmacología , Animales , Células Cultivadas , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genéticaRESUMEN
Claudin-2 enhances breast cancer liver metastasis and promotes the development of colorectal cancers. The objective of our current study is to define the regulatory mechanisms controlling Claudin-2 expression in breast cancer cells. We evaluated the effect of several Src Family Kinase (SFK) inhibitors or knockdown of individual SFK members on Claudin-2 expression in breast cancer cells. We also assessed the potential effects of pan-SFK and SFK-selective inhibitors on the formation of breast cancer liver metastases. This study reveals that pan inhibition of SFK signaling pathways significantly elevated Claudin-2 expression levels in breast cancer cells. In addition, our data demonstrate that pan-SFK inhibitors can enhance breast cancer metastasis to the liver. Knockdown of individual SFK members reveals that loss of Yes or Fyn induces Claudin-2 expression; whereas, diminished Lyn levels impairs Claudin-2 expression in breast cancer cells. The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis. Our findings may have major clinical implications and advise against the treatment of breast cancer patients with broad-acting SFK inhibitors and support the use of Lyn-specific inhibitors.
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Carcinoma/secundario , Claudinas/biosíntesis , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/secundario , Neoplasias Mamarias Experimentales/patología , Terapia Molecular Dirigida , Proteínas de Neoplasias/fisiología , Neoplasias de la Mama Triple Negativas/patología , Familia-src Quinasas/fisiología , Animales , Apoptosis/efectos de los fármacos , Carcinoma/genética , Carcinoma/prevención & control , Línea Celular Tumoral , Claudinas/genética , Dasatinib/farmacología , Dasatinib/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Hepáticas/prevención & control , Neoplasias Mamarias Experimentales/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Regiones Promotoras Genéticas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-fos/fisiología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Transducción de Señal , Factor de Transcripción AP-1/fisiología , Transcripción Genética , Neoplasias de la Mama Triple Negativas/genética , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
INTRODUCTION: Breast cancer cells display preferences for specific metastatic sites including the bone, lung and liver. Metastasis is a complex process that relies, in part, on interactions between disseminated cancer cells and resident/infiltrating stromal cells that constitute the metastatic microenvironment. Distinct immune infiltrates can either impair the metastatic process or conversely, assist in the seeding, colonization and growth of disseminated cancer cells. METHODS: Using in vivo selection approaches, we previously isolated 4T1-derived breast cancer cells that preferentially metastasize to these organs and tissues. In this study, we examined whether the propensity of breast cancer cells to metastasize to the lung, liver or bone is associated with and dependent on distinct patterns of immune cell infiltration. Immunohistocytochemistry and immunohistofluorescence approaches were used to quantify innate immune cell infiltrates within distinct metastases and depletion of Gr1+ (Ly-6C and Ly-6G) or specifically Ly-6G+ cells was performed to functionally interrogate the role of Ly-6G+ infiltrates in promoting metastasis to these organs. RESULTS: We show that T lymphocytes (CD3+), myeloid-derived (Gr-1+) cells and neutrophils (Ly-6G+ or NE+) exhibit the most pronounced recruitment in lung and liver metastases, with markedly less recruitment within bone metastatic lesions. Interestingly, these infiltrating cell populations display different patterns of localization within soft tissue metastases. T lymphocytes and granulocytic immune infiltrates are localized around the periphery of liver metastases whereas they were dispersed throughout the lung metastases. Furthermore, Gr-1+ cell-depletion studies demonstrate that infiltrating myeloid-derived cells are essential for the formation of breast cancer liver metastases but dispensable for metastasis to the lung and bone. A specific role for the granulocytic component of the innate immune infiltrate was revealed through Ly-6G+ cell-depletion experiments, which resulted in significantly impaired formation of liver metastases. Finally, we demonstrate that the CD11b+/Ly-6G+ neutrophils that infiltrate and surround the liver metastases are polarized toward an N2 phenotype, which have previously been shown to enhance tumor growth and metastasis. CONCLUSIONS: Our results demonstrate that the liver-metastatic potential of breast cancer cells is heavily reliant on interactions with infiltrating Ly-6G+ cells within the liver microenvironment.
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Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Granulocitos/inmunología , Granulocitos/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Biomarcadores , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Quimiocinas/genética , Quimiocinas/metabolismo , Análisis por Conglomerados , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Granulocitos/metabolismo , Humanos , Inmunohistoquímica , Inmunofenotipificación , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Infiltración Neutrófila/inmunología , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Transcriptoma , Microambiente Tumoral/inmunologíaRESUMEN
Integrating signals from multiple receptors allows cells to interpret the physiological context in which a signal is received. Here we describe a mechanism for receptor crosstalk in which receptor-induced increases in actin dynamics lower the threshold for signalling by another receptor. We show that the Toll-like receptor ligands lipopolysaccharide and CpG DNA, which are conserved microbial molecules, enhance signalling by the B-cell antigen receptor (BCR) by activating the actin-severing protein cofilin. Single-particle tracking reveals that increased severing of actin filaments reduces the spatial confinement of the BCR within the plasma membrane and increases BCR mobility. This allows more frequent collisions between BCRs and greater signalling in response to low densities of membrane-bound antigen. These findings implicate actin dynamics as a means of tuning receptor signalling and as a mechanism by which B cells distinguish inert antigens from those that are accompanied by indicators of microbial infection.
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Actinas/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Animales , Immunoblotting , Ligandos , Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Transducción de Señal/fisiología , Receptores Toll-Like/metabolismoRESUMEN
We recently demonstrated that both murine and human carcinomas grow significantly slower in mice on low carbohydrate (CHO), high protein diets than on isocaloric Western diets and that a further reduction in tumor growth rates occur when the low CHO diets are combined with the cyclooxygenase-2 inhibitor, celecoxib. Following upon these studies, we asked herein what effect low CHO, high protein diets, with or without celecoxib, might have on tumor metastasis. In the highly metastatic 4T1 mouse mammary tumor model, a 15% CHO, high protein diet supplemented with celecoxib (1 g/kg chow) markedly reduced lung metastases. Moreover, in longer-term studies using male Transgenic Adenocarcinoma of the Mouse Prostate mice, which are predisposed to metastatic prostate cancer, the 15% CHO diet, with and without celecoxib (0.3 g/kg chow), gave the lowest incidence of metastases, but a more moderate 25% CHO diet containing celecoxib led to the best survival. Metabolic studies with 4T1 tumors suggested that the low CHO, high protein diets may be forcing tumors to become dependent on amino acid catabolism for survival/growth. Taken together, our results suggest that a combination of a low CHO, high protein diet with celecoxib substantially reduces metastasis.
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Dieta Baja en Carbohidratos , Proteínas en la Dieta/farmacología , Metástasis de la Neoplasia/tratamiento farmacológico , Pirazoles/farmacología , Sulfonamidas/farmacología , Animales , Celecoxib , Dietoterapia/métodos , Modelos Animales de Enfermedad , Neoplasias Pulmonares/dietoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Metástasis de la Neoplasia/terapia , Neoplasias de la Próstata/dietoterapia , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
This paper presents a tactile vision substitution system (TVSS) for the study of active sensing. Two algorithms, namely image processing and trajectory tracking, were developed to enhance the capability of conventional TVSS. Image processing techniques were applied to reduce the artifacts and extract important features from the active camera and effectively converted the information into tactile stimuli with much lower resolution. A fixed camera was used to record the movement of the active camera. A trajectory tracking algorithm was developed to analyze the active sensing strategy of the TVSS users to explore the environment. The image processing subsystem showed advantageous improvement in extracting object's features for superior recognition. The trajectory tracking subsystem, on the other hand, enabled accurately locating the portion of the scene pointed by the active camera and providing profound information for the study of active sensing strategy applied by TVSS users.