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In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) actin-based organelles in human colon cancer cells. Membrane organelle disassembly reflected specific phosphorylation of VASP Ser239, the cGMP/PKG preferred site, and rapid VASP removal from tumor cell protrusions. Importantly, VASP Ser239 phosphorylation inhibited the proteolytic function of invadopodia, reflected by suppression of the cancer cell ability to digest DQ-collagen IV embedded in Matrigel. These results demonstrate a previously unrecognized role for VASP Ser239 phosphorylation, a single intracellular biochemical reaction, as an effective mechanism which opposes tumor cell shape promoting colon cancer invasion and metastasis. Reconstitution of physiological cGMP circuitry through VASP, in turn, represents an attractive targeted approach for patients with colorectal cancer.
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Moléculas de Adhesión Celular/fisiología , Extensiones de la Superficie Celular/patología , Neoplasias del Colon/patología , Proteínas de Microfilamentos/fisiología , Fosfoproteínas/fisiología , Línea Celular Tumoral , Movimiento Celular , Forma de la Célula , Colágeno Tipo IV/metabolismo , Guanilato Ciclasa/fisiología , Humanos , Invasividad Neoplásica , Fosforilación , Transducción de SeñalRESUMEN
The current model of human breast cancer progression proposes a linear multi-step process which initiates as flat epithelial atypia (FEA), progresses to atypical ductal hyperplasia (ADH), evolves into DCIS and culminates in the potentially lethal stage of invasive ductal carcinoma. For several decades a major challenge to human breast cancer research has been the identification of the molecular alterations associated with the different stages of breast cancer progression. Until recently, progress in attaining this goal has been hampered by technical limitations associated with applying advanced molecular technologies to the microscopic preinvasive stages of breast tumorigenesis. Recent advances in comprehensive, high-throughput genetic, transcriptomic and epigenetic technologies in combination with advanced microdissection and ex vivo isolation techniques have provided for a more complete understanding of the complex molecular genetic and molecular biological inter-relationships of the different stages of human breast cancer evolution. Here we review the molecular biological data suggesting that breast cancer develops and evolves along two distinct molecular genetic pathways. We also briefly review gene expression and epigenetic data that support the view of the tumour microenvironment as an important co-conspirator rather than a passive bystander during human breast tumorigenesis.
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Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Modelos Genéticos , Células Madre Neoplásicas/patologíaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Neoplasias Hepáticas/secundario , Mastectomía , Receptor ErbB-2 , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias de la Mama/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Carboplatino/administración & dosificación , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/cirugía , Docetaxel , Femenino , Humanos , Imagen por Resonancia Magnética , Terapia Neoadyuvante , Estadificación de Neoplasias , Taxoides/administración & dosificación , TrastuzumabRESUMEN
BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is characterized by the presence of circulating autoantibodies, hypergammaglobulinemia, necroinflammatory histology, and a response to immunosuppressive drugs. The goal of this retrospective study was to determine whether the presence of antinuclear antibodies (ANAs) or anti-smooth muscle antibodies (ASMAs) in patients with AIH correlated with clinical presentation, histologic findings, or response to immunosuppressive therapy. METHODS: Fifty-two patients diagnosed with AIH, on the basis of the revised scoring system of International Autoimmune Hepatitis group, were reviewed. Data on age, gender, aminotransferase levels, autoantibody titers, treatment regimens, and response to treatment were recorded. Seropositivity was defined as ANA >1:40 or ASMA >1:40. Percutaneous liver biopsies obtained at the initial presentation were reviewed. RESULTS: Forty-two patients with AIH (81%) were seropositive, and 10 (19%) were seronegative. Both groups were similar with respect to demographics, treatment regimens, and response to therapy. Histologic parameters were similar among the 2 groups, including portal and lobular inflammation, piecemeal necrosis, and centrilobular necrosis. There were no significant differences in aminotransferase levels at diagnosis or after treatment. CONCLUSIONS: The prevalence of ANAs or ASMAs did not correlate with the clinical or histologic severity of AIH at diagnosis. Furthermore, there was no correlation between antibody status and response to immunosuppressive therapy. Therefore, patients who meet the diagnosis of AIH on the basis of the revised scoring system of International Autoimmune Hepatitis Group should be given immunosuppressive therapy, regardless of antibody status.
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Autoanticuerpos/sangre , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/patología , Inmunosupresores/uso terapéutico , Hígado/patología , Adulto , Anciano , Animales , Femenino , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/fisiopatología , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Necrosis/patología , Estudios Retrospectivos , Estadística como Asunto , Transaminasas/sangre , Resultado del TratamientoRESUMEN
AIMS: The aim was to assess the value of GCC in distinguishing primary ovarian mucinous neoplasms from metastatic mucinous adenocarcinomas with ovarian involvement. Guanylyl cyclase C (GCC) is a brush border membrane receptor for the endogenous peptides guanylin and uroguanylin, and the homologous diarrhoeagenic bacterial heat-stable enterotoxins that is selectively expressed by epithelial cells from the duodenum to the rectum, but not by normal epithelia of the stomach or oesophagus, or normal extramucosal cells in humans. METHODS AND RESULTS: Fifty ovarian tumours: 27 primary ovarian mucinous neoplasms (seven cystadenomas, 10 borderline tumours and 10 cystadenocarcinomas) and 23 metastatic mucinous adenocarcinomas with ovarian involvement [13 colorectal adenocarcinomas, four gastric adenocarcinomas, six appendiceal mucinous tumours (four adenocarcinomas, one with neuroendocrine features, and two appendiceal mucinous cystadenomas)] were studied. For primary ovarian mucinous neoplasms, 25 of 27 were negative for GCC. Twelve of 13 cases of colorectal adenocarcinoma (except for one neuroendocrine adenocarcinoma) were positive for GCC. Three of four appendiceal mucinous adenocarcinomas were positive for GCC in both the primary and metastatic tumours (except for one neuroendocrine adenocarcinoma). Two of two appendiceal mucinous cystadenomas were positive for GCC. Of four cases of gastric adenocarcinoma with ovarian involvement, only one (primary tumour) exhibited focal GCC staining. CONCLUSIONS: GCC is a useful marker for differentiating between primary and secondary ovarian mucinous neoplasms.
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Adenocarcinoma Mucinoso , Biomarcadores de Tumor , Cistadenocarcinoma , Cistoadenoma Mucinoso , Guanilato Ciclasa/metabolismo , Neoplasias Ováricas , Receptores de Péptidos/metabolismo , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/secundario , Adulto , Anciano , Neoplasias del Apéndice/patología , Neoplasias Colorrectales/patología , Cistadenocarcinoma/secundario , Cistoadenoma Mucinoso/secundario , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología , Neoplasias Ováricas/secundario , Receptores de Enterotoxina , Receptores Acoplados a la Guanilato-Ciclasa , Estudios Retrospectivos , Neoplasias Gástricas/secundario , Carga TumoralRESUMEN
BACKGROUND AND AIMS: The benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) patients remains unclear, emphasizing the need for improved prognostic biomarkers to identify patients at risk of metastatic recurrence. To address this unmet clinical need, we examined the expression and phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP) in CRC tumor progression. VASP, a processive actin polymerase, promotes the formation of invasive membrane structures leading to extracellular matrix remodeling and tumor invasion. Phosphorylation of VASP serine (Ser) residues 157 and 239 regulate VASP function, directing subcellular localization and inhibiting actin polymerization, respectively. METHODS: The expression levels of VASP protein, pSer157-VASP, and pSer239-VASP were determined by immunohistochemistry in tumors and matched normal adjacent tissue from 141 CRC patients, divided into 2 cohorts, and the association of VASP biomarker expression with clinicopathologic features and disease recurrence was examined. RESULTS: We report that changes in VASP expression and phosphorylation were significantly associated with tumor invasion and disease recurrence. Furthermore, we disclose a novel 2-tiered methodology to maximize VASP positive and negative predictive value performance for prognostication. CONCLUSION: VASP biomarkers may serve as prognostic biomarkers in CRC and should be evaluated in a larger clinical study.
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Ductal carcinoma in situ (DCIS) of the breast is a lesion characterized by significant heterogeneity, in terms of morphology, immunohistochemical staining, molecular signatures, and clinical expression. For some patients, surgical excision provides adequate treatment, but a subset of patients will experience recurrence of DCIS or progression to invasive ductal carcinoma (IDC). Recent years have seen extensive research aimed at identifying the molecular events that characterize the transition from normal epithelium to DCIS and IDC. Tumor epithelial cells, myoepithelial cells, and stromal cells undergo alterations in gene expression, which are most important in the early stages of breast carcinogenesis. Epigenetic modifications, such as DNA methylation, together with microRNA alterations, play a major role in these genetic events. In addition, tumor proliferation and invasion is facilitated by the lesional microenvironment, which includes stromal fibroblasts and macrophages that secrete growth factors and angiogenesis-promoting substances. Characterization of DCIS on a molecular level may better account for the heterogeneity of these lesions and how this manifests as differences in patient outcome and response to therapy. Molecular assays originally developed for assessing likelihood of recurrence in IDC are recently being applied to DCIS, with promising results. In the future, the classification of DCIS will likely incorporate molecular findings along with histologic and immunohistochemical features, allowing for personalized prognostic information and therapeutic options for patients with DCIS. This review summarizes current data regarding the molecular characterization of DCIS and discusses the potential clinical relevance.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Carcinoma/genética , Animales , Biomarcadores de Tumor/análisis , Biopsia , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma/química , Carcinoma/patología , Carcinoma Intraductal no Infiltrante/química , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/terapia , Progresión de la Enfermedad , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Mastectomía , Técnicas de Diagnóstico Molecular , Recurrencia Local de Neoplasia , Fenotipo , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
A case of multifocal epithelioid angiosarcoma of the femur, tibia, fibula, and astragalus in a 54-year-old man is reported. The tumor was composed of nests and cords of malignant cells with epithelioid morphology, with foci of vascular differentiation, necrosis, and hemorrhage. By immunohistochemistry, the neoplastic cells showed positivity for endothelial cell markers (CD31, CD34, factor VIII-related antigen, and Ulex europaeus agglutinin I), epithelial markers (cytokeratins and epithelial membrane antigen), and vimentin. The authors' findings point out the need for a panel of antibodies for the careful search of histologic features of vascular differentiation to correctly diagnose vascular bone tumors with epithelioid features, especially in evaluating small core biopsy specimens in which a sheetlike rather than obviously vasoformative architecture may lead to an erroneous diagnosis of metastatic carcinoma.
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Células Epiteliales/patología , Hemangiosarcoma/patología , Biomarcadores/análisis , Diagnóstico Diferencial , Endotelio Vascular/patología , Hemangiosarcoma/química , Hemangiosarcoma/diagnóstico , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/patología , Vimentina/análisisRESUMEN
Adrenal cysts are rare and are often found incidentally during abdominal imaging for another reason. We describe two cases of adrenal cysts, one of which was found to be a cystic pheochromocytoma. Most cystic pheochromocytomas are not diagnosed by urinary screening studies, and the first indication of a pheochromocytoma may be hemodynamic instability during resection. We review the literature on adrenal cysts and make recommendations for the management of cystic adrenal masses.
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Enfermedades de las Glándulas Suprarrenales/cirugía , Neoplasias de las Glándulas Suprarrenales/cirugía , Quistes/cirugía , Feocromocitoma/cirugía , Enfermedades de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adulto , Quistes/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Feocromocitoma/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish "metabolic parasites", like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted "antibiotics" to selectively starve cancer cells. Our results provide new support for the "seed and soil" hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget.
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Antineoplásicos/farmacología , Metabolismo Energético/fisiología , Regulación Neoplásica de la Expresión Génica/fisiología , Modelos Biológicos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Oncogenes/fisiología , Microambiente Tumoral/fisiología , Acetilcisteína/farmacología , Caveolina 1/metabolismo , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Descubrimiento de Drogas , Células Epiteliales , Citometría de Flujo , Glucosa/metabolismo , Humanos , Recambio Mitocondrial/efectos de los fármacos , Proteínas Oncogénicas/metabolismo , Oncogenes/genética , Especies Reactivas de Oxígeno/metabolismo , Células del EstromaRESUMEN
Breast cancer is a common source of systemic metastatic disease. Distinguishing metastatic breast cancer from other types of malignancies can be diagnostically challenging but is important for correct treatment and prognosis. Nonmammary tumors can also metastasize to the breast, although this is a rare phenomenon. Differentiating a metastasis to the breast from a primary breast cancer can likewise be difficult. Knowledge of the clinical history and careful morphologic evaluation are the cornerstones of diagnosis. A panel of immunohistochemical stains tailored to the differential diagnosis at hand can provide helpful information in ambiguous cases.
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Mutations in the BRCA1 tumor suppressor gene are commonly found in hereditary breast cancer. Similarly, downregulation of BRCA1 protein expression is observed in the majority of basal-like breast cancers. Here, we set out to study the effects of BRCA1 mutations on oxidative stress in the tumor microenvironment. To mimic the breast tumor microenvironment, we utilized an in vitro co-culture model of human BRCA1-mutated HCC1937 breast cancer cells and hTERT-immortalized human fibroblasts. Notably, HCC1937 cells induce the generation of hydrogen peroxide in the fibroblast compartment during co-culture, which can be inhibited by genetic complementation with the wild-type BRCA1 gene. Importantly, treatment with powerful antioxidants, such as NAC and Tempol, induces apoptosis in HCC1937 cells, suggesting that microenvironmental oxidative stress supports cancer cell survival. In addition, Tempol treatment increases the apoptotic rates of MDA-MB-231 cells, which have wild-type BRCA1, but share a basal-like breast cancer phenotype with HCC1937 cells. MCT4 is the main exporter of L-lactate out of cells and is a marker for oxidative stress and glycolytic metabolism. Co-culture with HCC1937 cells dramatically induces MCT4 protein expression in fibroblasts, and this can be prevented by either BRCA1 overexpression or by pharmacological treatment with NAC. We next evaluated caveolin-1 (Cav-1) expression in stromal fibroblasts. Loss of Cav-1 is a marker of the cancer-associated fibroblast (CAF) phenotype, which is linked to high stromal glycolysis, and is associated with a poor prognosis in numerous types of human cancers, including breast cancers. Remarkably, HCC1937 cells induce a loss of Cav-1 in adjacent stromal cells during co-culture. Conversely, Cav-1 expression in fibroblasts can be rescued by administration of NAC or by overexpression of BRCA1 in HCC1937 cells. Notably, BRCA1-deficient human breast cancer samples (9 out of 10) also showed a glycolytic stromal phenotype, with intense mitochondrial staining specifically in BRCA1-deficient breast cancer cells. In summary, loss of BRCA1 function leads to hydrogen peroxide generation in both epithelial breast cancer cells and neighboring stromal fibroblasts, and promotes the onset of a reactive glycolytic stroma, with increased MCT4 and decreased Cav-1 expression. Importantly, these metabolic changes can be reversed by antioxidants, which potently induce cancer cell death. Thus, antioxidant therapy appears to be synthetically lethal with a BRCA1-deficiency in breast cancer cells and should be considered for future cancer prevention trials. In this regard, immunostaining with Cav-1 and MCT4 could be used as cost-effective biomarkers to monitor the response to antioxidant therapy.
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Antioxidantes/farmacología , Proteína BRCA1/metabolismo , Glucólisis , Estrés Oxidativo , Microambiente Tumoral/efectos de los fármacos , Acetilcisteína/farmacología , Apoptosis/efectos de los fármacos , Proteína BRCA1/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/prevención & control , Caveolina 1/metabolismo , Línea Celular , Técnicas de Cocultivo , Óxidos N-Cíclicos/farmacología , Femenino , Humanos , Peróxido de Hidrógeno/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Mutación , Marcadores de Spin , Regulación hacia Arriba/efectos de los fármacosRESUMEN
While bile acids are a risk factor for tumorigenesis induced by reflux disease, the mechanisms by which they contribute to neoplasia remain undefined. Here, we reveal that in gastroesophageal junction (GEJ) cells bile acids activate a tissue-specific developmental program defining the intestinal epithelial cell phenotype characterizing GEJ metaplasia. Deoxycholic acid (DCA) inhibited phosphorylation of EGF receptors (EGFRs) suppressing the proto-oncogene AKT. Suppression of EGFRs and AKT by DCA actuated an intestine-specific cascade in which NF-kappaB transactivated the tissue-specific transcription factor CDX2. In turn, CDX2 orchestrated a lineage-specific differentiation program encompassing genes characterizing intestinal epithelial cells. Conversely, progression from metaplasia to invasive carcinoma in patients, universally associated with autonomous activation of EGFRs and/or AKT, was coupled with loss of this intestinal program. Thus, bile acids induce intestinal metaplasia at the GEJ by activating the lineage-specific differentiation program involving suppression of EGFR and AKT, activating the NF-kappaB-CDX2 axis. Induction of this axis provides the context for lineage-addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF-kappaB signaling, amplifying tumorigenic programs.
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Adenocarcinoma/patología , Ácidos y Sales Biliares/química , Receptores ErbB/metabolismo , Neoplasias Esofágicas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/patología , Ácidos y Sales Biliares/metabolismo , Biopsia , Línea Celular Tumoral , Linaje de la Célula , Ácido Desoxicólico/química , Guanilato Ciclasa/química , Humanos , Ligandos , FN-kappa B/metabolismo , Fosforilación , Proto-Oncogenes Mas , Receptores de Enterotoxina , Receptores Acoplados a la Guanilato-Ciclasa , Receptores de Péptidos/químicaRESUMEN
Cancer mucosa antigens are emerging as a new category of self-antigens expressed normally in immunologically privileged mucosal compartments and universally by their derivative tumors. These antigens leverage the established immunologic partitioning of systemic and mucosal compartments, limiting tolerance opposing systemic antitumor efficacy. An unresolved issue surrounding self-antigens as immunotherapeutic targets is autoimmunity following systemic immunization. In the context of cancer mucosa antigens, immune effectors to self-antigens risk amplifying mucosal inflammatory disease promoting carcinogenesis. Here, we examined the relationship between immunotherapy for systemic colon cancer metastases targeting the intestinal cancer mucosa antigen guanylyl cyclase C (GCC) and its effect on inflammatory bowel disease and carcinogenesis in mice. Immunization with GCC-expressing viral vectors opposed nascent tumor growth in mouse models of pulmonary metastasis, reflecting systemic lineage-specific tolerance characterized by CD8(+), but not CD4(+), T-cell or antibody responses. Responses protecting against systemic metastases spared intestinal epithelium from autoimmunity, and systemic GCC immunity did not amplify chemically induced inflammatory bowel disease. Moreover, GCC immunization failed to promote intestinal carcinogenesis induced by germ-line mutations or chronic inflammation. The established role of CD8(+) T cells in antitumor efficacy, but CD4(+) T cells in autoimmunity, suggests that lineage-specific responses to GCC are particularly advantageous to protect against systemic metastases without mucosal inflammation. These observations support the utility of GCC-targeted immunotherapy in patients at risk for systemic metastases, including those with inflammatory bowel disease, hereditary colorectal cancer syndromes, and sporadic colorectal cancer.
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Antígenos de Neoplasias/inmunología , Neoplasias del Colon/inmunología , Neoplasias del Colon/terapia , Guanilato Ciclasa/inmunología , Receptores de Péptidos/inmunología , Linfocitos T/inmunología , Animales , Antígenos de Neoplasias/administración & dosificación , Autoantígenos/administración & dosificación , Autoantígenos/inmunología , Femenino , Guanilato Ciclasa/administración & dosificación , Inmunidad Mucosa/inmunología , Inmunización/métodos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores de Enterotoxina , Receptores Acoplados a la Guanilato-Ciclasa , Receptores de Péptidos/administración & dosificaciónRESUMEN
BACKGROUND AND AIMS: The most commonly lost gene products in colorectal carcinogenesis include guanylin and uroguanylin, endogenous ligands for guanylyl cyclase C (GCC). Beyond intestinal fluid balance, GCC mediates diarrhea induced by bacterial enterotoxins, and an inverse relationship exists between enterotoxigenic Escherichia coli infections producing the exogenous GCC ligand ST and colorectal cancer worldwide. However, the role of GCC in neoplasia remains obscure. METHODS: Intestinal tumorigenesis was examined in wild-type (Gcc(+/+)) and GCC-deficient (Gcc(-/-)) mice carrying mutations in Apc (Apc(Min/+)) or exposed to the carcinogen azoxymethane. Markers of DNA damage, loss of Apc heterozygosity, and beta-catenin mutations were used to assess genomic integrity. Hyperproliferation was explored using Ki67 and cell cycle markers. Apoptosis was quantified by transferase biotin-dUTP nick end labeling analysis. RESULTS: In colons of Apc(Min/+) mice, deletion of Gcc increased tumor incidence and multiplicity, reflecting uncoupling of loss of genomic integrity and compensatory apoptosis. Conversely, in the small intestine, elimination of Gcc increased tumorigenesis by enhancing proliferation without altering genomic integrity. Moreover, these distinct but mutually reinforcing mechanisms collaborate in azoxymethane-exposed mice, and deletion of Gcc increased tumor initiation and growth associated with hypermutation and hyperproliferation, respectively, in conjunction with attenuated apoptosis. CONCLUSIONS: GCC suppresses tumor initiation and growth by maintaining genomic integrity and restricting proliferation. This previously unrecognized role of GCC in inhibiting tumorigenesis, together with the invariant disruption in guanylin and uroguanylin expression early in carcinogenesis, and the uniform over-expression of GCC by tumors, underscores the potential of oral administration of GCC ligands for targeted prevention and therapy of colorectal cancer.