RESUMO
NANOG is a stem cell transcription factor that is essential for embryonic development, reprogramming normal adult cells and malignant transformation and progression. The nearly identical retrogene NANOGP8 is expressed in multiple cancers, but generally not in normal tissues and its function is not well defined. Our postulate is that NANOGP8 directly modulates the stemness of individual human colorectal carcinoma (CRC) cells. Stemness was measured in vitro as the spherogenicity of single CRC cells in serum-free medium and the size of the side population (SP) and in vivo as tumorigenicity and experimental metastatic potential in NOD/SCID mice. We found that 80% of clinical liver metastases express a NANOG with 75% of the positive metastases containing NANOGP8 transcripts. In all, 3-62% of single cells within six CRC lines form spheroids in serum-free medium in suspension. NANOGP8 is translated into protein. The relative expression of a NANOG gene increased 8- to 122-fold during spheroid formation, more than the increase in OCT4 or SOX2 transcripts with NANOGP8 the more prevalent family member. Short hairpin RNA (shRNA) to NANOG not only inhibits spherogenicity but also reduces expression of OCT4 and SOX2, the size of the SP and tumor growth in vivo. Inhibition of NANOG gene expression is associated with inhibition of proliferation and decreased phosphorylation of G2-related cell-cycle proteins. Overexpression of NANOGP8 rescues single-cell spherogenicity when NANOG gene expression is inhibited and increases the SP in CRC. Thus, NANOGP8 can substitute for NANOG in directly promoting stemness in CRC.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína Homeobox Nanog , Metástase Neoplásica , Esferoides Celulares , Células Tumorais CultivadasRESUMO
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, with few effective therapeutic options for advanced disease. At least 40% of HCCs are clonal, potentially arising from STAT3+, NANOG+ and OCT3/4+ liver progenitor/stem cell transformation, along with inactivation of transforming growth factor-beta (TGF-beta) signaling. Here we report significantly greater signal transducer and activator of transcription 3 (STAT3) and tyrosine phosphorylated STAT3 in human HCC tissues (P<0.0030 and P<0.0455, respectively) than in human normal liver. Further, in HCC cells with loss of response to TGF-beta, NSC 74859, a STAT3-specific inhibitor, markedly suppresses growth. In contrast, CD133(+) status did not affect the response to STAT3 inhibition: both CD133(+) Huh-7 cells and CD133(-) Huh-7 cells are equally sensitive to NSC 74859 treatment and STAT3 inhibition, with an IC(50) of 100 muM. Thus, the TGF-beta/beta2 spectrin (beta2SP) pathway may reflect a more functional 'stem/progenitor' state than CD133. Furthermore, NSC 74859 treatment of Huh-7 xenografts in nude mice significantly retarded tumor growth, with an effective dose of only 5 mg/kg. Moreover, NSC 74859 inhibited tyrosine phosphorylation of STAT3 in HCC cells in vivo. We conclude that inhibiting interleukin 6 (IL6)/STAT3 in HCCs with inactivation of the TGF-beta/beta2SP pathway is an effective approach in management of HCCs. Thus, IL6/STAT3, a major signaling pathway in HCC stem cell renewal and proliferation, can provide a novel approach to the treatment of specific HCCs.
Assuntos
Ácidos Aminossalicílicos , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Antígeno AC133 , Ácido Aminossalicílico/uso terapêutico , Animais , Antígenos CD/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Feminino , Glicoproteínas/metabolismo , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases. We investigated the effect of surgery plus postoperative (adjuvant) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction. METHODS: A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per day, plus 20 mg of leucovorin per square meter per day, for five days, followed by 4500 cGy of radiation at 180 cGy per day, given five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per day) plus leucovorin (20 mg per square meter per day) were given one month apart. RESULTS: The median overall survival in the surgery-only group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4 toxic effects occurred in 32 percent. CONCLUSIONS: Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection.
Assuntos
Adenocarcinoma/cirurgia , Antimetabólitos Antineoplásicos/uso terapêutico , Junção Esofagogástrica/cirurgia , Fluoruracila/uso terapêutico , Neoplasias Gástricas/cirurgia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Feminino , Fluoruracila/efeitos adversos , Gastrectomia , Humanos , Leucovorina/uso terapêutico , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/radioterapia , Taxa de SobrevidaRESUMO
Galectin-3 is a beta-galactoside-binding protein which regulates many biological processes including cell adhesion, migration, cell growth, tumor progression, metastasis, and apoptosis. Although the exact function of galectin-3 in cancer development is unclear, galectin-3 expression is associated with neoplastic progression and metastatic potential. Since studies have suggested that tumor cell survival in microcirculation determines the metastatic outcome, we examined the effect of galectin-3 overexpression in human breast carcinoma cell survival using the liver ischemia/reperfusion metastasis model. While the majority of control cells died by hepatic ischemia/reoxygenation, nearly all of galectin-3 overexpressing cells survived. We showed that galectin-3 inhibits nitrogen free radical-mediated apoptosis, one of the major death pathways induced during hepatic ischemia/reperfusion. Galectin-3 inhibition of apoptosis involved protection of mitochondrial integrity, inhibition of cytochrome c release and caspase activation. Taking these results together with the previous observation that galectin-3 inhibits apoptosis induced by loss of cell adhesion, we propose that galectin-3 is a critical determinant for anchorage-independent and free radical-resistant cell survival during metastasis.
Assuntos
Antígenos de Diferenciação/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Neoplasias da Mama/fisiopatologia , Carcinoma/fisiopatologia , Óxido Nítrico/fisiologia , Animais , Antígenos de Diferenciação/fisiologia , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Carcinoma/complicações , Carcinoma/patologia , Carcinoma/secundário , Sobrevivência Celular/efeitos dos fármacos , Feminino , Galectina 3 , Humanos , Isquemia/mortalidade , Isquemia/fisiopatologia , Circulação Hepática , Camundongos , Camundongos Nus , Traumatismo por Reperfusão/fisiopatologia , Células Tumorais CultivadasRESUMO
Tumor cells that express a fusion gene of Escherichia coli cytosine deaminase (CD) and herpes simplex virus type 1 thymidine kinase (TK) sequences activate and are subsequently killed by the nontoxic prodrugs 5-fluorocytosine and ganciclovir. We have previously developed a recombinant adenovirus containing the CD-TK fusion gene controlled by the human inducible heat shock protein 70 promoter so that heat at 41 degrees C for 1 hour induces therapeutic gene expression. This adenovirus effectively transduces heat-inducible expression of the CD-TK gene into human prostate carcinoma cells. However, because a limited number of cells in a tumor can actually be infected, we created a replicating adenoviral vector to increase CD-TK gene expression. This vector is a replication-competent, E1B-attenuated adenoviral vector containing the hsp70 promoter-driven CD-TK gene (Ad.E1A(+)HS-CDTK). When human prostate adenocarcinoma DU-145 cells (mutant p53) were infected with the virus at a multiplicity of infection (MOI) of 1 or 10, the viral replication was detected within 2 days at both MOIs. Similar results were observed in human colorectal carcinoma CX-1 cells. When DU-145 cells were infected with the virus at an MOI of 10, incubated for 24 hours, heated at 41 degrees C for 4 hours, and then harvested 20 hours later, Western blot analysis demonstrated that this virus successfully produced viral E1A proteins and heat shock stimulated the CD-TK gene expression by 12.3-fold. In addition, Ad.E1A(+)HS-CDTK effectively suppressed cell proliferation by viral cytopathic effect). Unlike with a replication-incompetent virus (Ad.HS-CDTK), the cytopathic effect of the virus and cytotoxicity in the presence of the prodrugs were still observed even at low MOI (MOI=1.0).
Assuntos
Adenoviridae/genética , Técnicas de Transferência de Genes , Terapia Genética/métodos , Temperatura Alta , Western Blotting , Sobrevivência Celular , Neoplasias Colorretais/metabolismo , Citosina Desaminase , Escherichia coli/enzimologia , Genes p53/genética , Vetores Genéticos , Proteínas de Choque Térmico HSP70/genética , Humanos , Masculino , Nucleosídeo Desaminases/metabolismo , Fenótipo , Pró-Fármacos/farmacologia , Regiões Promotoras Genéticas , Neoplasias da Próstata/metabolismo , Temperatura , Timidina Quinase/metabolismo , Fatores de Tempo , Células Tumorais CultivadasRESUMO
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo-2L) is a recently characterized member of the family of programmed cell death-inducing ligands that includes TNF-alpha and CD95L (FasL). It is well known that TRAIL binds to the death signaling receptors, DR4 and DR5, and initiates the TRAIL death pathway. Activation of this pathway, mediated through a caspase cascade, causes apoptosis. In this study, we hypothesized that oxidative stress facilitates TRAIL-induced apoptosis by promoting caspase activity through cytochrome c release from mitochondria. Human colorectal carcinoma CX-1 cells were treated with various concentrations of TRAIL (12.5-200 ng/ml) and/or sodium nitroprusside (SNP; 0.03-1 mM) for 12 h. SNP, a nitric oxide donor, which had little toxic effect by itself, enhanced TRAIL-induced cytotoxicity. For example, TRAIL-induced apoptosis (200 ng/ml) was increased by a factor of 2.5-fold in the presence of 1 mM SNP. The combined treatment also caused an increase in cytochrome c release, caspase-3 activity, and PARP cleavage. Overexpression of Bcl-2 completely blocked the SNP-promoting effects, but only moderately inhibited TRAIL-induced apoptosis. Similar results were observed in the presence of hydrogen peroxide or peroxynitrite. Taken together, the present studies suggest that SNP enhances TRAIL-induced cytotoxicity by facilitating the mitochondria-mediated caspase signal transduction pathway.
Assuntos
Apoptose , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Glicoproteínas de Membrana/farmacologia , Mitocôndrias/metabolismo , Nitroprussiato/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Reguladoras de Apoptose , Caspases/metabolismo , Sobrevivência Celular , Grupo dos Citocromos c/metabolismo , Sinergismo Farmacológico , Humanos , Glicoproteínas de Membrana/genética , Modelos Biológicos , Óxido Nítrico/metabolismo , Estresse Oxidativo , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/genéticaRESUMO
OBJECTIVE: To update the 1997 clinical practice guidelines for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast and colorectal cancers. These guidelines are intended for use in the care of patients outside of clinical trials. OPTIONS: Six tumor markers for colorectal cancer and eight for breast cancer were considered. They could be recommended or not for routine use or for special circumstances. In addition to carcinoembryonic antigen (CEA) and CA 15-3, CA 27.29 was also considered among the serum tumor markers for breast cancer. OUTCOMES: In general, the significant health outcomes identified for use in making clinical practice guidelines (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used. EVIDENCE: A computerized literature search from 1994 to March 1999 was performed. VALUES: The same values for use, utility, and levels of evidence were used by the committee. BENEFITS, HARMS, AND COSTS: The same benefit, harms, and costs were used. RECOMMENDATION: Changes were recommended (see Appendix). VALIDATION: The updated recommendations were validated by external review by the American Society of Clinical Oncology's (ASCO's) Health Services Research Committee and by ASCO's Board of Directors. SPONSOR: American Society of Clinical Oncology.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Neoplasias Colorretais/patologia , Adulto , Idoso , Biomarcadores Tumorais/economia , Biomarcadores Tumorais/normas , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Análise Custo-Benefício , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Resultado do TratamentoRESUMO
Our hypothesis is that rotation increases apoptosis in standard tissue culture medium at shear stresses of greater than approximately 0.3 dyn/cm2. Human MIP-101 poorly differentiated colorectal carcinoma cells were cultured for 6 d in complete medium in monolayers, on Teflon-coated nonadherent surfaces (static three-dimensional [3D]) or in rotating 3D cultures either in microgravity in low-earth orbit (3D microg) or in unit gravity on the ground (3D 1g). Apoptosis (determined morphologically), proliferation (by MIB1 staining), and the expression of epidermal growth-factor receptor (EGF-R), TGF-alpha, or TGF-beta were assessed by immunohistochemistry, while the expression of the differentiation marker carcinoembryonic antigen (CEA) was assessed on Western blots. Over the course of 6 d, static 3D cultures displayed the highest rates of proliferation and lowest apoptosis. This was associated with high EGF-R, TGF-alpha, and TGF-beta expression which was greater than that of a monolayer culture. Both rotated 3D lg and 3D microg cultures displayed lower expression of EGF-R, TGF-alpha, or TGF-beta and proliferation than that of monolayer or static 3D cultures. However, rotated 3D microg displayed significantly less apoptosis and greater CEA expression than rotated 3D 1g cultures. When rotated cultures of MIP-101 cells were grown uncler static conditions for another 3 d, proliferation increased and apoptosis decreased. Thus, rotation appears to increase apoptosis and decrease proliferation, whereas static 3D cultures in either unit or microgravity have less apoptosis, and reduced rotation in microgravity increases CEA expression.
Assuntos
Apoptose , Técnicas de Cultura de Células , Diferenciação Celular , Neoplasias Colorretais/patologia , Células Tumorais Cultivadas/citologia , Ausência de Peso , Reatores Biológicos , Antígeno Carcinoembrionário/análise , Adesão Celular , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Divisão Celular , Tamanho Celular , Neoplasias Colorretais/química , Meios de Cultura , Receptores ErbB/análise , Humanos , Rotação , Fator de Crescimento Transformador alfa/análise , Fator de Crescimento Transformador beta/análise , Células Tumorais Cultivadas/químicaRESUMO
BACKGROUND: Interleukin-6 (IL-6) is an important proinflammatory cytokine that has multiple effects on stimulating inflammation and cell growth. Experimental data suggest that carcinoembryonic antigen (CEA) induces the systemic production of IL-6 and that IL-6 may stimulate tumor cell growth at metastatic sites. We tested the hypothesis that blood concentrations of IL-6 are associated with the amount of circulating CEA and with prognosis in patients with colorectal cancer. METHODS: CEA and IL-6 concentrations were measured by using enzyme immunoassay in preoperative serum samples from 208 patients with stages I through IV colorectal cancer. RESULTS: Linear regression analysis showed a significant association between serum values of CEA and IL-6 (r = .544; R2 = .296; P < .001). Patients with stage III and stage IV disease had a significantly higher IL-6 serum concentration than those with stage I and stage II disease. In patients with stages I through III, 5-year survival was 83% in cases with concentrations of IL-6 at 10 pg/ml or less (n = 94) and 56% in cases with IL-6 concentrations of more than 10 pg/ml (n = 54; P = .001; median follow-up time, 46 months). By using multivariate analysis, an IL-6 concentration of more than 10 pg/ml was an independent prognostic factor of survival (relative risk = 1.820; P = .020). CONCLUSIONS: In patients with colorectal cancer, blood concentration of IL-6 is associated with high circulating CEA and advanced stage. Furthermore, an IL-6 concentration of more than 10 pg/ml is an independent negative prognostic marker of survival.
Assuntos
Antígeno Carcinoembrionário/sangue , Neoplasias do Colo/sangue , Interleucina-6/sangue , Neoplasias Retais/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Resultado do TratamentoRESUMO
Microscopic infarcts develop within the livers of athymic nude mice during the first 24 h after human colorectal carcinoma (CRC) cells arrest within hepatic sinusoids. Because these regions are reperfused, essentially all weakly metastatic clone A and MIP-101 CRC cells die, whereas many highly metastatic CX-1 CRC cells survive. Because hepatic sinusoidal endothelial cells kill tumor cells in vitro by producing nitric oxide, superoxide anion, and other reactive oxygen and nitrogen species, our purpose was to determine whether reoxygenation of ischemic hepatic cultures in vitro forms toxic oxygen and nitrogen radicals that kill weakly but not highly metastatic CRC cells. CRC cells (10(7)) were labeled with rhodamine-dextran and calcein AM, cultured with cells from one mouse liver in a rotating suspension culture system for up to 24 h, and the metabolic activity of the CRC cells was determined. Liver fragments oxygenated normally before harvest were not toxic to either CRC cell line, but coculture with liver made ischemic by a 3-min ligation of the portal vein and hepatic artery in vivo before harvest and then cultured in oxygenated medium killed 50-70% of weakly metastatic clone A and MIP-101 cells at 24 h but <15% of highly metastatic CX-1 cells. Inhibition of nitric oxide synthase, addition of exogenous superoxide dismutase, but not catalase or hypoxia, during coculture blocked the killing of weakly metastatic CRC cells. Thus, reoxygenation of hepatic parenchymal and nonparenchymal cells after ischemia may form toxic species that eliminate weakly metastatic CRCs within 24 h of their arrest in the liver.
Assuntos
Neoplasias Colorretais/patologia , Fígado/patologia , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Humanos , Isquemia/metabolismo , Isquemia/patologia , Fígado/irrigação sanguínea , Fígado/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias/patologia , Óxido Nítrico/metabolismo , Células Tumorais CultivadasRESUMO
Carcinoembryonic antigen (CEA) injected intravenously into athymic nude mice increases the ability of weakly metastatic human colorectal carcinoma (CRC) cells to colonize liver in an experimental metastasis assay. Since CEA acts as an intercellular adhesion molecule in vitro, several investigators have postulated that this facilitation of experimental metastasis may be mediated through adhesion between CEA on CRC and CEA-binding proteins on Kupffer or other cells lining the hepatic sinusoid. The present work tested this postulate both by intravital fluorescence videomicroscopy in vivo and in adhesion assays in vitro to enriched populations of Kupffer cells and hepatic sinusoidal endothelial cells (SEC). The data indicate that CEA expression does not effect adhesion to enriched Kupffer cells or SEC in vitro. These data suggest that CEA enhances liver colonization through another mechanism, possibly one that involves modulation of the hepatic response to tumor cell implantation.
Assuntos
Antígeno Carcinoembrionário/imunologia , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Metástase Neoplásica/imunologia , Animais , Adesão Celular/imunologia , Neoplasias Colorretais/imunologia , Humanos , Células de Kupffer/imunologia , Células de Kupffer/patologia , Neoplasias Hepáticas/imunologia , Masculino , Camundongos , Camundongos NusRESUMO
BACKGROUND: The Commission on Cancer data from the National Cancer Data Base (NCDB) examining current time trends (1985-1995) in stage of disease, treatment patterns, and survival relating to patients with rectal adenocarcinoma are described in this report. METHODS: Seven calls for data to hospital cancer registries across the U.S. have yielded a total of 5,850,000 cancer cases for the years 1985-1995 and include 20,461 rectal and rectosigmoid junction adenocarcinoma cases in 1985-1986, 36,007 cases in 1989-1990, and 42,069 cases in 1994-1995. These data represent 24.4%, 44.5%, and 52.5%, respectively, of the estimated cases of rectal and rectosigmoid adenocarcinoma cases diagnosed in the U.S. in each of the 3 respective time periods. Analysis of the data is limited to cases with American Joint Committee on Cancer (AJCC) Stage I-IV disease. RESULTS: Four trends were observed. 1) Stage I disease was diagnosed with decreasing frequency, decreasing from 37.1% of cases with known AJCC stage of disease in 1985-1986 to 33.8% in 1994-1995. 2) There was an increase in the frequency with which local excision was utilized as all or part of the primary treatment for Stage I disease. 3) Stage for stage, there was an increase in the frequency with which anterior/posterior resections were utilized and a corresponding decline in the use of abdominoperineal resections. 4) Multimodal treatment regimens are being used with greater frequency, particularly in patients with Stage II and III disease. CONCLUSIONS: The NCDB data have important implications for analyzing cancer treatment and outcome in the U.S. These data suggest that rectal adenocarcinoma is being diagnosed at a later stage, especially among the young and African Americans. The guidelines for colorectal carcinoma screening issued by the American Cancer Society and the American Gastroenterological Association should be promoted more vigorously to increase the proportion of patients presenting with early stage disease and improve overall survival. The increased use of multimodal therapy for the treatment of Stage II and III disease continues.
Assuntos
Adenocarcinoma/terapia , Bases de Dados Factuais , Neoplasias Retais/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Demografia , Etnicidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Padrões de Prática Médica , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
Guidelines from two major organizations have recently supported the use of only the serological marker carcinoembryonic antigen (CEA) for the prognostication and monitoring of patients with colorectal carcinoma. However, in view of the exciting advances made recently in elucidating the molecular and cellular biology of adenocarcinoma of the rectum, the molecules that transform the well-ordered normal rectal epithelium into an invasive adenocarcinoma may yield information about the ultimate behavior of that cancer. Consequently, assessing the expression of molecules within a primary cancer may predict the probability of regional and distant metastasis, response to therapy, and outcome. This review analyzes the current state of intratumoral expression of several molecular markers for the management of rectal cancer and evaluates their potential for defining which patients may undergo rectal sphincter preservation and need adjuvant therapy.
Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais , Neoplasias Retais/patologia , Adenocarcinoma/genética , Antígeno Carcinoembrionário/análise , Transformação Celular Neoplásica , Regulação Neoplásica da Expressão Gênica , Genes DCC , Genes p53/genética , Humanos , Ploidias , Prognóstico , Neoplasias Retais/genéticaRESUMO
OBJECTIVE: To update the analysis of technical and biologic factors related to hepatic resection for colorectal metastasis in a large single-institution series to identify important prognostic indicators and patterns of failure. SUMMARY BACKGROUND DATA: Surgical therapy for colorectal carcinoma metastatic to the liver is the only potentially curable treatment. Careful patient selection of those with resectable liver-only metastatic disease is crucial to the success of surgical therapy. METHODS: Two hundred forty-four consecutive patients undergoing curative hepatic resection for metastatic colorectal carcinoma were analyzed retrospectively. Variables examined included sex, stage of primary lesion, size of liver lesion(s), number of lesions, disease-free interval, ploidy, differentiation, preoperative carcinoembryonic antigen level, and operative factors such as resection margin, use of cryotherapy, intraoperative ultrasound, and blood loss. RESULTS: Surgical margin, number of lesions, and carcinoembryonic antigen (CEA) levels significantly control prognosis. Patients with only one or two liver lesions, a 1-cm surgical margin, and low CEA levels have a 5-year disease-free survival rate of more than 30%. Disease-free interval, original stage, bilobar involvement, size of metastasis, differentiation, and ploidy were not significant predictors of recurrence. The pattern of failure correlates with surgical margin. Routine use of intraoperative ultrasound resulted in an increased incidence of negative surgical margin during the period examined. CONCLUSIONS: Surgical resection or cryotherapy of hepatic metastasis from colorectal cancer is safe and curable in appropriately selected patients. Biologic factors, such as number of lesions and carcinoembryonic antigen levels, determine potential curability, and surgical margin governs the patterns of failure and outcome in potentially curable patients. Optimization of selection criteria and surgical resection margins will improve outcome.
Assuntos
Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/cirurgia , Criocirurgia , Intervalo Livre de Doença , Seguimentos , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Morbidade , Valor Preditivo dos Testes , Prognóstico , Estudos RetrospectivosRESUMO
Human colorectal carcinoma (CRC) cell survival for the first 24 h after implantation in the hepatic sinusoid determines its potential to colonize the liver. Nearly 10-fold more highly metastatic CX-1 cells survive within the livers of nude mice 24 h after intrasplenic injection than weakly metastatic clone A cells. Because CRCs contact sinusoidal endothelial cells (SECs) during implantation, we sought to determine whether SECs were more toxic to clone A than to CX-1 cells. When 2 x 10(4) vital dye-labeled CRC cells were added to murine SEC monolayers, more than 30% of clone A cells lost calcein AM fluorescence compared to fewer than 5% of CX-1 cells after 24 h of coculture with SECs. Kupffer cells did not mediate this effect, because neither enriched Kupffer cells nor SECs treated with a Kupffer cell inhibitor altered the SEC-mediated toxic effect to clone A cells. Pretreatment with a nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine, superoxide dismutase, or dexamethasone, blocked SEC-mediated toxicity to clone A cells, whereas calcium chelation and catalase did not. In addition, clone A cells were more sensitive to a superoxide donor, 3-morpholinosydnonimine N-ethylcarbamide, than were CX-1 cells, and neither cell line was sensitive to sodium nitroprusside, a nitric oxide donor. Thus, unstimulated murine SECs produce reactive oxygen species that are selectively toxic to weakly metastatic clone A cells. This may be a mechanism by which host liver cells eliminate weakly metastatic neoplastic cells.
Assuntos
Carcinoma/patologia , Comunicação Celular/fisiologia , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Fígado/citologia , Óxido Nítrico/fisiologia , Superóxidos/metabolismo , Animais , Carcinoma/metabolismo , Sobrevivência Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura , Neoplasias Colorretais/metabolismo , Endotélio/citologia , Endotélio/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Fígado/metabolismo , Masculino , Camundongos , Óxido Nítrico Sintase/antagonistas & inibidores , Superóxidos/antagonistas & inibidores , Células Tumorais CultivadasRESUMO
As many as a third of patients with rectal cancers may be candidates for sphincter preservation surgery. The goal of the conservative management of adenocarcinoma of the distal rectum is to preserve rectal sphincter function without sacrificing local tumor control. To achieve this goal, a combined modality approach is necessary because multimodality therapy for more advanced disease has improved both local control and survival. Candidates for local excision are those with adenocarcinomas with a maximal diameter of less than 4 cm, mobile, and not poorly differentiated or mucinous and within 10 cm of the anal verge--usually within 6 cm. These criteria should be defined objectively by biopsy combined with state-of-the-art endorectal imaging. Newer molecular markers that are associated with prognosis and response to therapy may also be important for assessing prognosis, probability of local recurrence, and whether conservative treatment is appropriate. Patients with T0-3 N0 lesions meeting these standard clinicopathologic criteria have been treated successfully with wide local excision combined with chemotherapy and radiotherapy. Patients with larger or more advanced lesions may undergo low anterior resection with coloanal anastomosis. After resection, radiotherapy to at least 45 to 50 Gy is delivered to the pelvis and tumor bed often with concomitant chemotherapy. The overall rate of local failure in prospective single-institution trials in which local excision is performed with postoperative chemoradiotherapy has been 5% for T1 lesions, 7% for T2 lesions and 24% for T3 lesions. Although single-institution studies have supported the concept of conservative therapy, the safety and efficacy of this approach must still be confirmed in a multicenter, prospective trial, such as that underway in several of the cooperative oncology groups, before it may be considered a standard of practice.
Assuntos
Adenocarcinoma/cirurgia , Canal Anal/fisiologia , Neoplasias Retais/cirurgia , Adenocarcinoma/patologia , Adenocarcinoma Mucinoso/cirurgia , Canal Anal/cirurgia , Anastomose Cirúrgica/métodos , Biomarcadores Tumorais/análise , Biópsia , Quimioterapia Adjuvante , Protocolos Clínicos , Colo/cirurgia , Terapia Combinada , Diagnóstico por Imagem , Humanos , Biologia Molecular , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Seleção de Pacientes , Probabilidade , Prognóstico , Estudos Prospectivos , Dosagem Radioterapêutica , Radioterapia Adjuvante , Neoplasias Retais/patologia , Indução de Remissão , Segurança , Taxa de SobrevidaRESUMO
Molecular prognostic markers are molecules produced by either the tumor or the host (patient) whose expression is associated with the clinical outcome. Three types of molecular markers exist that characterize different aspects of the tumor : host relationship: (1) tumor biology, (2) tumor burden and (3) host response. The first type of marker is measured within the primary or metastatic tumor mass and defines the aggressiveness of the cancer and its ability to respond to therapy. The other two types of markers are usually measured in the blood and assess concentrations of circulating tumor products or cytokines that may be involved in host resistance to the cancer. In this brief review we will define each type of marker, provide examples of their current utility and then describe how these markers may be useful.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/diagnóstico , Apoptose , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Humanos , Neovascularização PatológicaRESUMO
BACKGROUND: The National Cancer Data Base (NCDB), a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, is a cancer management and outcomes data base for health care organizations. It provides a comparative summary of patient care that is used by communities and participating hospitals for self-assessment. The most current (1994) data are described here. METHODS: Six calls for data have yielded a total of 4,580,000 cases for the years 1985-1994. A total of 1735 hospital cancer registries have each participated in at least one of the calls for data. RESULTS: Summing the last year's report from each of the 1227 hospitals that participated in 1994, the cases represent the equivalent of 57% of the estimated 1994 U.S. cancer cases. These data were received from all six regions of the country, including all 50 states. Ninety-seven percent of patients received all or part of their treatment at the reporting hospital. The four most common cancers are carcinomas of the breast (15.7%), lung (14.3%), prostate (13.1%), and colon (7.7%), and collectively they comprise a majority of new cases. CONCLUSIONS: The NCDB is a cancer management and outcomes data base for health care organizations that currently provides data on 57% of the estimated new cases in the U.S. Past data have been used extensively to assess patterns of care and outcomes.
Assuntos
Bases de Dados Factuais/estatística & dados numéricos , Neoplasias/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , American Cancer Society , Criança , Pré-Escolar , Etnicidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sociedades Médicas , Estados Unidos/epidemiologiaRESUMO
Carcinoembryonic antigen (CEA) may promote experimental metastasis through production of cytokines. The effect of systemic CEA on the production of proinflammatory cytokines was investigated in mice and compared to levels induced by lipopolysaccharide (LPS). Serum concentrations of interleukin (IL)-6 peaked 1 h after an i.v. CEA injection of 40 microg/mouse to 37-54% of the maximal level induced by a 1 microg/mouse injection of LPS in both normal and immunoincompetent mice. The CEA induction of IL-6 was a specific response, because the peptide PELPK (the pentapeptide on CEA that is the ligand for the CEA receptor on Kupffer cells) conjugated to albumin induced 30% of the maximal CEA response for IL-6, whereas the specificity control PELGK-conjugated albumin did not. IL-1alpha and tumor necrosis factor (TNF)-alpha levels after i.v. injection of CEA were only 3-5% of those induced by LPS. The IL-6 responses of mice pretreated with 100 microg/kg genistein were decreased by more than 40%. However, genistein inhibited the TNF-alpha response to LPS by 46% but increased the CEA-induced response by 300%. When murine Kupffer cells were stimulated with LPS or CEA in vitro, LPS increased tyrosine phosphorylation of a Mr 30,000 protein, whereas CEA decreased phosphorylation of a Mr 60,000 protein and did not increase phosphorylation of the Mr 30,000 protein. Thus, i.v. CEA stimulates production of IL-6 and TNF-alpha after binding to Kupffer cells through signal transduction pathways that appear to be different from those stimulated by LPS.