Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
1.
Nature ; 511(7509): 319-25, 2014 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-25030168

RESUMEN

Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function.


Asunto(s)
Glicocálix/metabolismo , Glicoproteínas/metabolismo , Integrinas/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Animales , Mama/citología , Mama/metabolismo , Mama/patología , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Fibroblastos , Glicocálix/química , Humanos , Proteínas Inmovilizadas/química , Proteínas Inmovilizadas/metabolismo , Integrinas/química , Ratones , Terapia Molecular Dirigida , Mucina-1/metabolismo , Metástasis de la Neoplasia/patología , Células Neoplásicas Circulantes , Unión Proteica , Receptores de Superficie Celular
2.
Cell Rep Med ; 4(12): 101312, 2023 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-38086377

RESUMEN

Molecular subtyping of breast cancer is based mostly on HR/HER2 and gene expression-based immune, DNA repair deficiency, and luminal signatures. We extend this description via functional protein pathway activation mapping using pre-treatment, quantitative expression data from 139 proteins/phosphoproteins from 736 patients across 8 treatment arms of the I-SPY 2 Trial (ClinicalTrials.gov: NCT01042379). We identify predictive fit-for-purpose, mechanism-of-action-based signatures and individual predictive protein biomarker candidates by evaluating associations with pathologic complete response. Elevated levels of cyclin D1, estrogen receptor alpha, and androgen receptor S650 associate with non-response and are biomarkers for global resistance. We uncover protein/phosphoprotein-based signatures that can be utilized both for molecularly rationalized therapeutic selection and for response prediction. We introduce a dichotomous HER2 activation response predictive signature for stratifying triple-negative breast cancer patients to either HER2 or immune checkpoint therapy response as a model for how protein activation signatures provide a different lens to view the molecular landscape of breast cancer and synergize with transcriptomic-defined signatures.


Asunto(s)
Resistencia a Antineoplásicos , Neoplasias de la Mama Triple Negativas , Humanos , Resistencia a Antineoplásicos/genética , Terapia Neoadyuvante , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Biomarcadores , Perfilación de la Expresión Génica
3.
Cancer Cell ; 40(6): 609-623.e6, 2022 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-35623341

RESUMEN

Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR+ subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.


Asunto(s)
Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Humanos , Terapia Neoadyuvante , Receptor ErbB-2/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo
4.
Cancer Causes Control ; 22(1): 141-50, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21103921

RESUMEN

BACKGROUND: Nutritional factors are associated with reduced risk of prostate cancer progression, yet mechanisms remain unclear. We examined the effects of lycopene and fish oil supplements versus placebo on the normal prostate microenvironment, among men pursuing active surveillance for low-burden prostate cancer. We hypothesized that lycopene or fish oil supplements would down-regulate insulin-like growth factor-1 (IGF-1) and cyclooxygenase 2 (COX-2) gene expression, respectively, reflecting putative proliferation (IGF-1) and inflammatory (COX-2) pathways relevant to carcinogenesis. METHODS: We conducted a 3-month randomized, double-blinded, clinical trial comparing prostate tissue gene expression profiles (assessed by qRT-PCR) among men with favorable-risk prostate cancer receiving either 30 mg/day lycopene, 3 g/day fish oil (including 1,098 mg eicosapentaenoic and 549 mg docosahexaenoic fatty acids) or placebo. RESULTS: Among 69 men (22 assigned to lycopene, 21 to fish, and 26 to placebo), there was no difference in the change from baseline to the 3 months in IGF-1 expression level between the placebo and lycopene arms (p = 0.93) nor in COX-2 expression between the placebo and fish arms (p = 0.99). CONCLUSION: Compared to placebo, 3-month intervention with lycopene or fish oil did not significantly change IGF-1 and COX-2 gene expression in the normal prostate microenvironment in men with low-burden prostate cancer. Further analysis of global gene expression profiles may shed light on the bioactivity and relevance of these nutrients in prostate cancer.


Asunto(s)
Antiinflamatorios/uso terapéutico , Carotenoides/uso terapéutico , Ciclooxigenasa 2/biosíntesis , Suplementos Dietéticos , Aceites de Pescado/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Neoplasias de la Próstata/metabolismo , Método Doble Ciego , Perfilación de la Expresión Génica , Humanos , Licopeno , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/dietoterapia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espera Vigilante
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA