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Concern over climate change is growing in the healthcare space, and telemedicine has been rapidly expanding since the start of the COVID19 pandemic. Understanding the various sources of environmental emissions from clinic visits-both virtual and in-person-will help create a more sustainable healthcare system. This study uses a Life Cycle Assessment with retrospective clinical data from Stanford Health Care (SHC) in 2019-2021 to determine the environmental emissions associated with in-person and virtual clinic visits. SHC saw 13% increase in clinic visits, but due to the rise in telemedicine services, the Greenhouse Gas emissions (GHGs) from these visits decreased 36% between 2019 and 2021. Telemedicine (phone and video appointments) helped SHC avoid approximately 17,000 metric tons of GHGs in 2021. Some departments, such as psychiatry and cancer achieved greater GHG reductions, as they were able to perform more virtual visits. Telemedicine is an important component for the reduction of GHGs in healthcare systems; however, telemedicine cannot replace every clinic visit and proper triaging and tracking systems should be in place to avoid duplicative care.
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ShcA is an important mediator of ErbB2- and transforming growth factor ß (TGF-ß)-induced breast cancer cell migration, invasion, and metastasis. We show that in the context of reduced ShcA levels, the bone morphogenetic protein (BMP) antagonist chordin-like 1 (Chrdl1) is upregulated in numerous breast cancer cells following TGF-ß stimulation. BMPs have emerged as important modulators of breast cancer aggressiveness, and we have investigated the ability of Chrdl1 to block BMP-induced increases in breast cancer cell migration and invasion. Breast cancer-derived conditioned medium containing elevated concentrations of endogenous Chrdl1, as well as medium containing recombinant Chrdl1, suppresses BMP4-induced signaling in multiple breast cancer cell lines. Live-cell migration assays reveal that BMP4 induces breast cancer migration, which is effectively blocked by Chrdl1. We demonstrate that BMP4 also stimulated breast cancer cell invasion and matrix degradation, in part, through enhanced metalloproteinase 2 (MMP2) and MMP9 activity that is antagonized by Chrdl1. Finally, high Chrdl1 expression was associated with better clinical outcomes in patients with breast cancer. Together, our data reveal that Chrdl1 acts as a negative regulator of malignant breast cancer phenotypes through inhibition of BMP signaling.
Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Neoplasias da Mama/patologia , Meios de Cultivo Condicionados/farmacologia , Proteínas do Olho/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Morfogenética Óssea 4/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proteínas do Olho/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Proteínas do Tecido Nervoso/genética , Prognóstico , Fator de Crescimento Transformador beta/farmacologia , Regulação para CimaRESUMO
Breast carcinoma (BC) has been extensively profiled by high-throughput technologies for over a decade, and broadly speaking, these studies can be grouped into those that seek to identify patient subtypes (studies of heterogeneity) or those that seek to identify gene signatures with prognostic or predictive capacity. The sheer number of reported signatures has led to speculation that everything is prognostic in BC. Here, we show that this ubiquity is an apparition caused by a poor understanding of the interrelatedness between subtype and the molecular determinants of prognosis. Our approach constructively shows how to avoid confounding due to a patient's subtype, clinicopathological profile, or treatment profile. The approach identifies patients who are predicted to have good outcome at time of diagnosis by all available clinical and molecular markers but who experience a distant metastasis within 5 years. These inherently difficult patients (~7% of BC) are prioritized for investigations of intratumoral heterogeneity.
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Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Prognóstico , Análise de Sobrevida , TranscriptomaRESUMO
The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors.
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Resistencia a Medicamentos Antineoplásicos , Sistema de Sinalização das MAP Quinases , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Fosfatase 6 de Especificidade Dupla/genética , Fosfatase 6 de Especificidade Dupla/metabolismo , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Células HEK293 , Humanos , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
ShcA (SHC1) is an adapter protein that possesses an SH2 and a PTB phosphotyrosine-binding motif. ShcA generally uses its PTB domain to engage activated receptor tyrosine kinases (RTK), but there has not been a definitive determination of the role of this domain in tumorigenesis. To address this question, we employed a ShcA mutant (R175Q) that no longer binds phosphotyrosine residues via its PTB domain. Here, we report that transgenic expression of this mutant delays onset of mammary tumors in the MMTV-PyMT mouse model of breast cancer. Paradoxically, we observed a robust increase in the growth and angiogenesis of mammary tumors expressing ShcR175Q, which displayed increased secretion of fibronectin and expression of integrin α5/ß1, the principal fibronectin receptor. Sustained integrin engagement activated Src, which in turn phosphorylated proangiogenic RTKs, including platelet-derived growth factor receptor, fibroblast growth factor receptor, and Met, leading to increased VEGF secretion from ShcR175Q-expressing breast cancer cells. We defined a ShcR175Q-dependent gene signature that could stratify breast cancer patients with a high microvessel density. This study offers the first in vivo evidence of a critical role for intracellular signaling pathways downstream of the ShcA PTB domain, which both positively and negatively regulate tumorigenesis during various stages of breast cancer progression.
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Neoplasias da Mama/metabolismo , Fosfotirosina/metabolismo , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Fibronectinas/metabolismo , Humanos , Integrina alfa5beta1/metabolismo , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Mutação , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Estrutura Terciária de Proteína , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Adaptadoras da Sinalização Shc/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
INTRODUCTION: Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. METHODS: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture microdissected trephine biopsies of both breast cancer bone metastases and independent primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared with primary, bone-metastatic breast tumors. RESULTS: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary breast tumors. In addition, ABCC5 was significantly upregulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 substantially reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers in vivo. Finally, conditioned media from breast cancer cells with reduced ABCC5 expression failed to induce in vitro osteoclastogenesis to the same extent as conditioned media from breast cancer cells expressing ABCC5. CONCLUSIONS: Our data suggest that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis.
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Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Osteoclastos/patologia , Animais , Osso e Ossos/patologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Osteólise/genética , Interferência de RNA , RNA Interferente Pequeno , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: CT10 regulator of kinase (Crk) adaptor proteins (CrkI, CrkII and CrkL) play a role in integrating signals for migration and invasion of highly malignant breast cancer cell lines. This has important implications, as elevated CrkI/II protein levels were observed in a small cohort of breast cancer patients, which identified a potential role for Crk proteins in breast cancer progression. Numerous in vitro studies identified a role for Crk proteins in cell motility, but little is known about how Crk proteins contribute to breast cancer progression in vivo. METHODS: The clinical significance of Crk proteins in human breast cancer was assessed by analyzing published breast cancer datasets using a gene expression signature that was generated following CrkII over-expression and by examining Crk protein expression in tissue microarrays of breast tumors (n = 254). Stable knockdown of Crk (CrkI/CrkII/CrkL) proteins was accomplished using a short hairpin RNA (shRNA)-mediated approach in two basal breast cancer cell lines, MDA-231 1833TR and SUM1315, where the former have a high affinity to form bone metastases. Both in vitro assays (cell migration, invasion, soft agar growth) and in vivo experiments (intra-cardiac, tibial and mammary fat pad injections) were performed to assess the functional significance of Crk proteins in breast cancer. RESULTS: A gene signature derived following CrkII over-expression correlated significantly with basal breast cancers and with high grade and poor outcome in general. Moreover, elevated Crk immunostaining on tissue microarrays revealed a significant association with highly proliferative tumors within the basal subtype. RNAi-mediated knockdown of all three Crk proteins in metastatic basal breast cancer cells established a continued requirement for Crk in cell migration and invasion in vitro and metastatic growth in vivo. Furthermore, Crk ablation suppressed anchorage independent growth and in vivo orthotopic tumor growth. This was associated with diminished cell proliferation and was rescued by expression of non-shRNA targeted CrkI/II. Perturbations in tumor progression correlated with altered integrin signaling, including decreased cell spreading, diminished p130Cas phosphorylation, and Cdc42 activation. CONCLUSIONS: These data highlight the physiological importance of Crk proteins in regulating growth of aggressive basal breast cancer cells and identify Crk-dependent signaling networks as promising therapeutic targets.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-crk/metabolismo , Animais , Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteína Substrato Associada a Crk/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Integrinas/metabolismo , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica , Fosforilação , Interferência de RNA , RNA Interferente Pequeno , Proteína cdc42 de Ligação ao GTP/metabolismoRESUMO
Using transgenic mouse models of breast cancer that ablate Src homology and collagen A (ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4(+) T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T cell-deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers. Finally, we define a novel ShcA-regulated immune signature that functions as an independent prognostic marker of survival in human epidermal growth factor receptor 2(+) and basal breast cancers. We reveal a novel role for tumor cell-derived ShcA in the establishment and maintenance of an immunosuppressive state.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptores Proteína Tirosina Quinases/fisiologia , Proteínas Adaptadoras da Sinalização Shc/genética , Animais , Neoplasias da Mama/imunologia , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Terapia de Imunossupressão , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Paridade , Gravidez , Modelos de Riscos Proporcionais , RNA Neoplásico/genética , RNA Neoplásico/isolamento & purificação , Proteínas Adaptadoras da Sinalização Shc/deficiência , Proteínas Adaptadoras da Sinalização Shc/fisiologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/patologia , Resultado do TratamentoRESUMO
Thoracic radiotherapy may produce the morbidity-associated lung responses of alveolitis or fibrosing alveolitis in treated cancer patients. The genetic factors that influence a patient's likelihood of developing alveolitis and the relationship of this inflammatory response to the development of fibrosis are largely unknown. Herein we use genetic mapping to identify radiation-induced lung response susceptibility loci in reciprocal backcross mice bred from C3H/HeJ (alveolitis response) and C57BL/6J (fibrosing alveolitis/fibrosis response) strains. Mice were treated with 18-Gy whole thorax irradiation and their survival, lung histopathology, and bronchoalveolar lavage cell types were recorded. A genome-wide scan was completed using 139 markers. The C3H/HeJ alveolitis response included mast cell infiltration and increased neutrophil numbers in the lavage compared with the level in the C57BL/6J strain, which developed fibrosis. In backcross mice, posttreatment survival was dictated by the development of an alveolitis response with increased mast cell, bronchoalveolar lavage total cell, and neutrophil numbers. Fibrosis was measured only in a subset of mice developing alveolitis and, in these mice, was associated with neutrophil count. Genotyping revealed coinheritance of C3H alleles (chromosomes 2, 4, 19, and X) and C57BL/6J alleles (chromosomes 1, 7, 9, and 17) to result in higher fibrosis scores in backcross mice. Mice that inherited C57BL/6J alleles at the putative alveolitis susceptibility loci were spared this response and lived to the end of the experiment. In this animal model, independent loci control the development of alveolitis from fibrosis, whereas fibrosing alveolitis occurs with the coinheritance of these factors.
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Fibrose Pulmonar/patologia , Fibrose Pulmonar/radioterapia , Alelos , Animais , Lavagem Broncoalveolar , Cruzamentos Genéticos , Genoma , Genótipo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Fenótipo , Radioterapia/métodos , Especificidade da EspécieRESUMO
Cystic fibrosis (CF) transmembrane conductance regulator (Cftr) knockout mice present the clinical features of low body weight and intestinal disease permitting an assessment of the interrelatedness of these phenotypes in a controlled environment. To identify intestinal alterations that are affected by body weight in CF mice, the histological phenotypes of crypt-villus axis height, goblet cell hyperplasia, mast cell infiltrate, crypt cell proliferation, and apoptosis were measured in a population of 12-wk-old (C57BL/6 x BALB/cJ) F2 Cftr(tm1UNC) and non-CF mice presenting a range of body weight. In addition, cardiac blood samples were assessed, and gene expression profiling of the ileum was completed. Crypt-villus axis height decreased with increasing body weight in CF but not control mice. Intestinal crypts from CF mice had fewer apoptotic cells, per unit length, than did non-CF mice, and normalized cell proliferation was similar to control levels. Goblet cell hyperplasia and mast cell infiltration were increased in the CF intestine and identified to be independent of body weight. Blood triglyceride levels were found to be significantly lower in CF mice than in control mice but were not dependent on CF mouse weight. By expression profiling, genes of DNA replication and lipid metabolism were among those altered in CF mice relative to non-CF controls, and no differences in gene expression were measured between samples from CF mice in the 25th and 75th percentile for weight. In this CF mouse model, crypt elongation, due to an expanded proliferative zone and decreased apoptosis, was identified to be dependent on body weight.
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Fibrose Cística/genética , Íleo/patologia , Fenótipo , Animais , Apoptose , Glicemia/metabolismo , Peso Corporal/genética , Fibrose Cística/sangue , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Íleo/anatomia & histologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CFTR , Triglicerídeos/sangueRESUMO
Cystic fibrosis (CF) lung disease severity is influenced by unknown genetic factors apart from the disease causative gene, cystic fibrosis transmembrane conductance regulator (CFTR). Previous studies have shown the C57BL/6J congenic Cftr(-/-) (B6 CF) mouse to develop a fibrotic lung disease compared with both CF mice of the BALB/c background and wild-type animals. In this report, gene expression profiling with microarrays was used to identify genes differentially expressed in the lungs of B6 and BALB CF mice compared with non-CF littermates. Seven hundred two genes or expressed sequence tags (ESTs) were identified to be differentially expressed between the B6 CF and non-CF control lungs (P < 0.05), and, by Gene Ontology classification, the B6 CF response included the cell proliferation categories of DNA metabolism and mitosis. In the response of BALB mice to nonfunctional Cftr, 943 genes/ESTs were differentially expressed compared with controls. The biological processes of apoptosis and T and B cell proliferation were prominent in the gene list of the BALB CF strain. In support of this strain difference, increased T lymphocyte infiltration was evident in the lungs of BALB CF mice, through immunohistochemical staining, compared with the lungs from both B6 CF and non-CF control mice. Four hundred forty-four genes/ESTs were differentially expressed between B6 CF and BALB CF mice (P < 0.05, fold > 2), including 56 that map to previously identified linkage intervals. These results suggest that the variable severity of CF lung disease in this mouse model is controlled by multiple genetic factors, including those of an immune response.