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1.
Mol Nutr Food Res ; 64(1): e1900728, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31797544

RESUMO

BACKGROUND: Pandemic vitamin D deficiency is associated with insulin resistance and type 2 diabetes. Vitamin D supplementation has been reported to have improved glucose homeostasis. However, its mechanism to improve insulin sensitivity remains unclear. METHODS AND RESULTS: Male C57BL/6J mice are fed with/without vitamin D control (CD) or Western (WD) diets for 15 weeks. The vitamin-D-deficient lean (CDVDD) and obese (WDVDD) mice are further subdivided into two groups. One group is re-supplemented with vitamin D for 6 weeks and hepatic insulin signaling is examined. Both CD and WD mice with vitamin D deficiency developed insulin resistance. Vitamin D supplementation in CDVDD mice significantly improved insulin sensitivity, hepatic inflammation, and antioxidative capacity. The hepatic insulin signals like pAKT, pFOXO1, and pGSK3ß are increased and the downstream Pepck, G6pase, and Pgc1α are reduced. Furthermore, the lipogenic genes Srebp1c, Acc, and Fasn are decreased, indicating that hepatic lipid accumulation is inhibited. CONCLUSION: The results demonstrate that vitamin D deficiency induces insulin resistance. Its supplementation has significant beneficial effects on pathophysiological mechanisms in type 2 diabetes but only in lean and not in the obese phenotype. The increased subacute inflammation and insulin resistance in obesity cannot be significantly alleviated by vitamin D supplementation. This needs to be taken into consideration in the design of new clinical trials.

2.
Mol Med Rep ; 20(5): 4634-4644, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545494

RESUMO

In a number of types of cancer, anoikis, a form of apoptosis induced by loss of extracellular matrix (ECM) attachment, is disturbed. Anoikis resistance is essential in the formation of metastases. A recent study identified carcinoma cell subpopulations surviving without ECM contact in pathological specimens of colorectal cancer. The occurrence of these subpopulations indicated anoikis resistance. In the present study, it is demonstrated that KRAS and BRAF mutations induce anoikis resistance in colon cancer (Caco­2) cells. In 3D cultures, Caco­2 cells transfected with mutated KRAS or BRAF formed multicellular structures analogous to anoikis­resistant subpopulations in actual carcinomas, and serve as an in vitro model for anoikis resistance. Caco­2 cell lines were constructed, with KRAS or BRAF mutations, using retroviral delivery. The current study investigated anoikis resistance using an Annexin V apoptosis test from suspension cultures. 3D in vitro cultures, which were generated in collagen­matrigel mixtures, were assessed using confocal microscopy. 3D cultures embedded in paraffin were analyzed using conventional histopathology. In suspension cultures, Caco­2 cells with KRAS or BRAF mutations indicated a significantly lower proportion of Annexin positivity than the native Caco­2 cells, indicating that these mutations induce anoikis resistance in Caco­2 cells. 3D cultures displayed native Caco­2 cells forming polarized cysts with a single layer thick epithelium, whereas Caco­2 cells with KRAS or BRAF mutations formed partially filled cystic structures or solid round structures where only the outermost layer was in contact with the ECM. Additionally, KRAS mutations induced reversed polarity to Caco­2 cells along with the emergence of solid growth. The present study demonstrated that KRAS and BRAF mutations induce anoikis resistance in Caco­2 colorectal cancer cells. The growth patterns generated from the KRAS and BRAF mutated cells in 3D cultures revealed a resemblance to the putative anoikis­resistant subpopulations in actual carcinomas, including micropapillary structures and solid tumor cell islands. Additionally, KRAS mutation induced the emergence of inverted polarity. In conclusion, 3D cultures with modified Caco­2 cells serve as a valid in vitro model for anoikis resistance and inverted polarity.

3.
World J Gastroenterol ; 25(31): 4383-4404, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31496619

RESUMO

Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40% of colorectal cancer patients. The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation. While the low-level systemic inflammation is often clinically silent, its consequences are many and may ultimately lead to chronic cancer-associated wasting, cachexia. In this review, we discuss the pathogenesis of cancer-related systemic inflammation, explore the role of systemic inflammation in promoting cancer growth, escaping antitumor defense, and shifting metabolic pathways, and how these changes are related to less favorable outcome.

4.
Sci Rep ; 9(1): 11209, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371751

RESUMO

The dietary lignan metabolite, enterolactone, has been suggested to have anti-cancer functions, and high serum enterolactone concentrations have been associated with decreased risk of breast and prostate cancers. We hypothesized that serum enterolactone concentrations as a marker of plant-based foods are associated with decreased risk in colorectal cancer (CRC). We measured serum enterolactone glucuronide and sulfate concentrations by liquid chromatography-tandem mass spectrometry in 115 CRC patients and 76 sex- and age-matched controls and analyzed the results with respect to tumor parameters, clinical parameters, and systemic inflammatory markers. Patients with colon cancer had significant lower serum enterolactone glucuronide and sulfate concentrations than controls (glucuronide: median 3.14 nM vs. 6.32 nM, P < 0.001; sulfate: median 0.13 nM vs. 0.17 nM, P = 0.002), whereas rectal cancer patients had similar enterolactone levels as controls (glucuronide: median 5.39 nM vs. 6.32 nM, P = 0.357; sulfate: median 0.19 nM vs. 0.17 nM, P = 0.452). High serum enterolactone concentrations were associated with low tumor grade, high serum creatinine levels, and concomitant diabetes. In summary, our results suggest that serum enterolactone concentrations are decreased in colon but not in rectal cancer. Further investigations are required to assess whether this reflects an altered lignan metabolism by the colon microbiome.

5.
J Transl Med ; 17(1): 199, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196200

RESUMO

BACKGROUND: Platelets not only contribute to hemostasis but also to the regulation of inflammatory reactions and cancer pathogenesis. We hypothesized that blood platelet count would be associated with systemic inflammation, the densities of tumor infiltrating immune cells, and survival in colorectal cancer (CRC), and these relationships could be altered by aspirin use. METHODS: We measured blood platelet count in a cohort of 356 CRC patients and analyzed its relationships with tumor and patient characteristics including aspirin use, markers of systemic inflammation (modified Glasgow Prognostic Score, mGPS; serum levels of CRP, albumin, and 13 cytokines), blood hemoglobin levels, five types of tumor infiltrating immune cells (CD3, CD8, FoxP3, Neutrophil elastase, mast cell tryptase), and survival. RESULTS: Platelet count inversely correlated with blood hemoglobin levels (p < 0.001) and positively correlated with serum levels of CRP and multiple cytokines including IL-1RA, IL-4, IL-6, IL-7, IL-8, IL-12, IFNγ, and PDGF-BB (p < 0.001 for all), while aspirin use was not associated with the levels of systemic inflammatory markers. High platelet count was also associated with high mGPS (p < 0.001) but did not show statistically significant multivariable adjusted associations with the densities of tumor infiltrating immune cells. Higher platelet counts were observed in higher tumor stage (p < 0.001), but platelet count or aspirin use were not associated with patient survival. CONCLUSIONS: High platelet count is associated with systemic inflammation in CRC. This study could not demonstrate statistically significant associations between platelet count, aspirin use, and the densities of tumor infiltrating immune cells.

6.
APMIS ; 127(8): 561-569, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132191

RESUMO

Toll-like receptors (TLRs) are involved in colorectal cancer (CRC) pathogenesis. However, the significance of serum TLR concentrations in CRC is unknown. We analyzed serum TLR2 and TLR4 concentrations with ELISA in preoperative samples from 118 patients with CRC and 88 matched controls. We also assessed tissue TLR expression with immunohistochemistry and by detecting serum determinants of systemic inflammation. Most participants (>70%) had undetectable serum TLR2. The mean serum TLR4 levels were lower in patients than in controls (1.1 vs 1.8 ng/mL; p = 0.015). Undetectable TLR4 was more common in stage I (39%) than in stages II-IV (11%, p < 0.001). TLR2 or TLR4 expression in tumor cells did not correlate with serum levels, but abundant TLR2 expression in normal colon epithelium was associated with detectable serum TLR2 (p = 0.034). Undetectable serum TLR2 was linked to high modified Glasgow prognostic scores (p = 0.010), high CRP levels (p = 0.013), blood vessel invasion (p = 0.013), and tended to be associated with worse 5-year survival (p = 0.052). In conclusion, serum TLR2 levels were inversely associated with systemic inflammation in patients with CRC. Moreover, serum TLR2 levels might depend more on normal colorectal mucosa contributions than on tumor tissue contributions. Further studies are required to assess the prognostic value of serum TLR2.


Assuntos
Carcinoma/sangue , Neoplasias Colorretais/sangue , Mucosa Intestinal/patologia , Receptor 2 Toll-Like/sangue , Receptor 4 Toll-Like/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma/patologia , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Escala de Resultado de Glasgow , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Análise de Sobrevida
7.
Int J Cancer ; 145(3): 678-685, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653264

RESUMO

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide and the need for novel biomarkers and therapeutic strategies to improve diagnosis and surveillance is obvious. This study aims to identify ß6 -integrin (ITGB6) as a novel serum tumor marker for diagnosis, prognosis, and surveillance of CRC. ITGB6 serum levels were validated in retro- and prospective CRC patient cohorts. ITGB6 serum levels were analyzed by ELISA. Using an initial cohort of 60 CRC patients, we found that ITGB6 is present in the serum of CRC, but not in non-CRC control patients. A cut-off of ≥2 ng/mL ITGB6 reveals 100% specificity for the presence of metastatic CRC. In an enlarged study cohort of 269 CRC patients, ITGB6 predicted the onset of metastatic disease and was associated with poor prognosis. Those data were confirmed in an independent, prospective cohort consisting of 40 CRC patients. To investigate whether ITGB6 can also be used for tumor surveillance, serum ITGB6-levels were assessed in 26 CRC patients, pre- and post-surgery, as well as during follow-up visits. After complete tumor resection, ITGB6 serum levels declined completely. During follow-up, a new rise in ITGB6 serum levels indicated tumor recurrence or the onset of new metastasis as confirmed by CT scan. ITGB6 was more accurate for prognosis of advanced CRC and for tumor surveillance as the established marker carcinoembryonic antigen (CEA). Our findings identify ITGB6 as a novel serum marker for diagnosis, prognosis, and surveillance of advanced CRC. This might essentially contribute to an optimized patient care.


Assuntos
Neoplasias Colorretais/sangue , Cadeias beta de Integrinas/sangue , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Humanos , Cadeias beta de Integrinas/biossíntese , Cadeias beta de Integrinas/genética , Prognóstico , Estudo de Prova de Conceito , Modelos de Riscos Proporcionais , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reprodutibilidade dos Testes
9.
Br J Cancer ; 120(2): 238-246, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30563990

RESUMO

BACKGROUND: Cancer cachexia is a complex wasting syndrome affecting patients with advanced cancer, with systemic inflammation as a key component in pathogenesis. Protein degradation and release of amino acids (AAs) in skeletal muscle are stimulated in cachexia. Here, we define factors contributing to serum AA levels in colorectal cancer (CRC). METHODS: Serum levels of nine AAs were characterised in 336 CRC patients and their relationships with 20 markers of systemic inflammatory reaction, clinicopathological features of cancers and patient survival were analysed. RESULTS: Low serum glutamine and histidine levels and high phenylalanine levels associated with indicators of systemic inflammation, including high modified Glasgow Prognostic Score, high blood neutrophil/lymphocyte ratio and high serum levels of CRP, IL-6 and IL-8. Low levels of serum glutamine, histidine, alanine and high glycine levels also associated with advanced cancer stage and with poor cancer-specific survival in univariate analysis. CONCLUSIONS: In CRC, serum AA levels are associated with systemic inflammation and disease stage. These findings may reflect muscle catabolism induced by systemic inflammation in CRC.


Assuntos
Aminoácidos/sangue , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Citocinas/sangue , Inflamação/sangue , Idoso , Aminoácidos/classificação , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Inflamação/complicações , Inflamação/patologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutrófilos/patologia , Prognóstico
10.
Int J Endocrinol ; 2018: 2059481, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425741

RESUMO

Objective: Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. Design and Methods: Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980-2010. Results: Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p = 0.002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p < 0.001). Seventy-one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. Conclusions: The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas.

11.
Clin Epigenetics ; 10(1): 141, 2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413173

RESUMO

BACKGROUND: Altered methylation patterns are driving forces in colorectal carcinogenesis. The serrated adenocarcinoma (SAC) and sporadic colorectal carcinoma showing histological and molecular features of microsatellite instability (hmMSI-H) are two endpoints of the so-called serrated pathological route sharing some characteristics but displaying a totally different immune response and clinical outcome. However, there are no studies comparing the methylome of these two subtypes of colorectal carcinomas. The methylation status of 450,000 CpG sites using the Infinium Human Methylation 450 BeadChip array was investigated in 48 colorectal specimens, including 39 SACs and 9 matched hmMSI-H. RESULTS: Microarray data comparing SAC and hmMSI-H showed an enrichment in functions related to morphogenesis, neurogenesis, cytoskeleton, metabolism, vesicle transport and immune response and also significant differential methylation of 1540 genes, including CD14 and HLA-DOA which were more methylated in hmMSI-H than in SAC and subsequently validated at the CpG, mRNA and protein level using pyrosequencing, quantitative polymerase chain reaction (qPCR) and immunohistochemistry. CONCLUSIONS: These results demonstrate particular epigenetic regulation patterns in SAC which may help to define key molecules responsible for the characteristic weak immune response of SAC and identify potential targets for treating SAC, which lacks molecular targeted therapy.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/patologia , Metilação de DNA , Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Ilhas de CpG , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade
12.
Br J Cancer ; 119(2): 213-219, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29808017

RESUMO

BACKGROUND: Matrix metalloproteinase-8 (MMP-8) is a protease mainly expressed by neutrophils that cleaves numerous substrates, including collagens and cytokines. We have previously shown that serum MMP-8 levels increase in colorectal cancer (CRC) and correlate with distant metastasis. However, short follow-up in our prospective cohort did not enable survival analyses at the time of the first publication. METHODS: Preoperative serum MMP-8 levels were measured by immunofluorometric assay in 271 CRC patients and related to clinicopathological parameters, markers of systemic inflammation (modified Glasgow Prognostic Score, mGPS; serum levels of C-reactive protein (CRP), albumin and 13 cytokines), the density of six types of tumour-infiltrating immune cells and survival. RESULTS: Increased MMP-8 levels associated with higher mGPS and higher serum levels of CRP and several cytokines, including IL-1ra, IL-7 and IL-8 (p < 0.001 for all). Serum MMP-8 negatively correlated with tumour-infiltrating mast cells (invasive margin: p = 0.005, tumour centre: p = 0.010). The patients with high-serum MMP-8 levels (>100 ng/mL) had poor cancer-specific survival, independent of tumour stage, grade, lymphatic invasion, patient age, BRAF VE1 immunohistochemistry, mismatch repair deficiency, Immunoscore and mGPS (multivariate HR 2.12, 95% CI 1.21-3.71, p = 0.009). CONCLUSIONS: High-serum MMP-8 levels are associated with systemic inflammation and adverse outcome in CRC.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Inflamação/sangue , Metaloproteinase 8 da Matriz/sangue , Idoso , Proteína C-Reativa/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Inflamação/patologia , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-7/sangue , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética
13.
Carcinogenesis ; 39(6): 788-797, 2018 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-29701748

RESUMO

Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1+/-) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC.


Assuntos
Colo/metabolismo , Neoplasias do Colo/genética , Mucosa Intestinal/metabolismo , Proteína 1 Homóloga a MutL/deficiência , Animais , Neoplasias do Colo/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Feminino , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Heterozigoto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Instabilidade de Microssatélites , Mitose/genética
14.
Sci Rep ; 8(1): 1126, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29348549

RESUMO

Anemia is common in colorectal cancer (CRC) but its relationships with tumor characteristics, systemic inflammation, and survival have not been well characterized. In this study, blood hemoglobin levels and erythrocyte mean corpuscular volume (MCV) levels were measured in two independent cohorts of 148 CRC patients and 208 CRC patients, and their correlation with patient and tumor characteristics, systemic inflammatory markers (modified Glasgow Prognostic Score: mGPS; serum levels of thirteen cytokines, C-reactive protein, albumin), and survival were analyzed. We found that anemia, most frequently normocytic, followed by microcytic, was present in 43% of the patients. Microcytic anemia was most commonly associated with proximal colon tumor location. Average MCV and blood hemoglobin levels were lower in tumors with high T-class. Low blood hemoglobin associated with systemic inflammation, including high mGPS and high serum levels of C-reactive protein and IL-8. Particularly, normocytic anemia associated with higher mGPS. Normocytic anemia associated with a tendency towards worse overall survival (multivariate hazard ratio 1.61, 95% confidence interval 1.07-2.42, p = 0.023; borderline statistical significance considering multiple hypothesis testing). In conclusion, anemia in CRC patients is most frequently normocytic. Proximal tumor location is associated with predominantly microcytic anemia and systemic inflammation is associated with normocytic anemia.


Assuntos
Anemia/etiologia , Neoplasias Colorretais/complicações , Idoso , Idoso de 80 Anos ou mais , Anemia/diagnóstico , Biomarcadores , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/terapia , Terapia Combinada , Feminino , Humanos , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Período Pré-Operatório , Prognóstico
15.
J Neuropathol Exp Neurol ; 76(10): 848-853, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922847

RESUMO

We previously reported a patient who had developed 2 glioblastomas at the age of 54 and 64 years, respectively. The first glioblastoma in the right frontal lobe was treated with surgery and radiotherapy. Ten years later, the patient developed a second, left frontal glioblastoma. Discordant patterns of TP53 and PTEN mutations suggested that the second tumor was not a recurrence but an independently developed glioblastoma. To determine the molecular mechanism underlying this enigmatic case with 10-year survival, we performed whole-exome sequencing. We found that both tumors were IDH-wildtype, excluding the possibility of secondary glioblastomas that developed from a less malignant astrocytic precursor lesion. We here report that the patient carried a heterozygous germline mutation [c.3305_3306insT; p.1102-fs-insT(Gly1105/TrpfsX3)] in the MSH6 mismatch repair gene. Further sequencing revealed that in addition to the germline MSH6 mutation, the first glioblastoma showed loss of the MSH6 wild-type allele, and the second glioblastoma carried a somatic MSH6 mutation [c.1403G>A; p.Arg468His]. Our results indicate that both glioblastomas had 2 hits in the MSH6 gene, and that loss of MSH6 function was the key event in the pathogenesis of these 2 independent primary glioblastomas.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa/genética , Glioblastoma/genética , Adulto , Idoso , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Saúde da Família , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade
16.
World J Gastroenterol ; 23(26): 4831-4838, 2017 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-28765705

RESUMO

AIM: To characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa. METHODS: We analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed. RESULTS: Normal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours. CONCLUSION: Tumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.


Assuntos
Carcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Neoplasias Colorretais/mortalidade , Progressão da Doença , Feminino , Finlândia/epidemiologia , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade
17.
Sci Rep ; 7(1): 5374, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28710487

RESUMO

Recent studies have reported of an association between high serum apolipoprotein A1 (APOA1) levels and favorable prognosis in several malignancies, while the significance of apolipoprotein B (APOB) in cancer is less well-known. In this study, we analyzed the correlation between serum APOA1 and APOB levels, and APOB/APOA1 ratio, and their associations with clinicopathologic parameters, the levels of twenty systemic inflammatory markers, and survival in 144 colorectal cancer (CRC) patients. We demonstrated that low serum APOA1 levels associated with advanced T-class and TNM-stage but low serum APOB levels did not significantly correlate with tumor characteristics. Serum APOA1 levels showed strong negative correlation with the markers of systemic inflammation including serum CRP and interleukin (IL)-8 levels and blood neutrophil count, whereas high serum APOB levels associated with high serum CCL2 levels. High APOA1 and APOB levels and low APOB/APOA1 ratio associated with improved cancer specific and overall survival. APOA1 had independent prognostic value in Cox regression analysis. In conclusion, low serum APOA1 levels are associated with advanced stage and systemic inflammation, while serum APOB does not significantly correlate with tumor stage. Serum APOA1 represents a promising additional prognostic parameter in CRC.


Assuntos
Apolipoproteína A-I/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Síndrome de Resposta Inflamatória Sistêmica/mortalidade , Síndrome de Resposta Inflamatória Sistêmica/patologia , Idoso , Apolipoproteínas B/sangue , Neoplasias Colorretais/complicações , Neoplasias Colorretais/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Soro/química , Análise de Sobrevida
18.
Sci Rep ; 7: 45057, 2017 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-28327550

RESUMO

Collagen XVII and integrin α6ß4 have well-established roles as epithelial adhesion molecules. Their binding partner laminin 332 as well as integrin α6ß4 are largely recognized to promote invasion and metastasis in various cancers, and collagen XVII is essential for the survival of colon and lung cancer stem cells. We have studied the expression of laminin γ2, collagen XVII and integrin ß4 in tissue microarray samples of squamous cell carcinoma (SCC) and its precursors, actinic keratosis and Bowen's disease. The expression of laminin γ2 was highest in SCC samples, whereas the expression of collagen XVII and integrin ß4 varied greatly in SCC and its precursors. Collagen XVII and integrin ß4 were also expressed in SCC cell lines. Virus-mediated RNAi knockdown of collagen XVII and integrin ß4 reduced the migration of less aggressive SCC-25 cells in horizontal scratch wound healing assay. Additionally, in a 3D organotypic myoma invasion assay the loss of collagen XVII or integrin ß4 suppressed equally the migration and invasion of SCC-25 cells whereas there was no effect on the most aggressive HSC-3 cells. Variable expression patterns and results in migration and invasion assays suggest that collagen XVII and integrin ß4 contribute to SCC tumorigenesis.


Assuntos
Autoantígenos/metabolismo , Carcinoma de Células Escamosas/metabolismo , Integrina beta4/metabolismo , Colágenos não Fibrilares/metabolismo , Animais , Doença de Bowen/genética , Doença de Bowen/metabolismo , Doença de Bowen/patologia , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Inativação de Genes , Humanos , Laminina/metabolismo , Camundongos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
19.
Sci Rep ; 6: 36519, 2016 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-27819306

RESUMO

Deficiency of vitamin D is associated with increased risk of several types of cancer including colorectal cancer (CRC). However, factors contributing to low levels of 25-hydroxyvitamin D [25(OH)D] in CRC are not clear. Therefore, in this study serum 25(OH)D levels in 117 CRC patients and 86 controls were analyzed and correlated with the clinicopathological data including morphological subtype (serrated or conventional), quantity of tumor infiltrating immune cells, levels of systemic inflammatory markers, and disease outcome. We found that the patients had lower serum 25(OH)D levels compared to the controls. Interestingly, among the patients mismatch repair deficiency, serrated morphology, and high body mass index associated with lowest serum 25(OH)D levels. In addition, patients operated in summer or autumn had higher serum 25(OH)D levels. Furthermore, serum 25(OH)D levels inversely correlated with several systemic inflammatory markers, e.g. serum C reactive protein, but did not associate with prognosis. Mechanism leading to vitamin D deficiency in these patients are not clear but could be related to the effects of systemic inflammation. Longitudinal studies are warranted to assess vitamin D deficiency as a potential risk factor for serrated colorectal polyps and adenocarcinoma.


Assuntos
Neoplasias Colorretais/sangue , Inflamação/sangue , Inflamação/etiologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Vitamina D/sangue , Deficiência de Vitamina D/metabolismo
20.
Virchows Arch ; 469(4): 395-404, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27421843

RESUMO

Serrated colorectal adenocarcinoma (SAC) is a morphologically distinct subtype of colorectal cancer (CRC), in which increased HIF-1α mRNA expression and HIF-1α protein stabilization are typical features. Here we aimed to further elucidate HIF-1α protein expression in serrated and non-serrated colorectal carcinomas (CRCs) and their precursor lesions and its association with vascular endothelial growth factor (VEGF) and microvascular density (MVD). HIF-1α and VEGF expressions were determined immunohistochemically in 134 serrated polyps (SPs), 104 non-serrated adenomas (NSAs), 81 SACs, and 74 matched conventional adenocarcinomas (CCs) and were correlated with morphology, clinicopathological features, and MVD. In premalignant lesions, both HIF-1α and VEGF were expressed in the vast majority of SPs and NSAs. In CRCs, HIF-1α protein was also present in 77.8 % of SACs, while only 20.3 % of CCs were HIF-1α proficient. MVD was significantly higher in SACs, but the serrated morphology was the only significant predictor of MVD in CRC in multivariate analyses. HIF-1α protein is often stabilized in well-vascularized SACs, suggesting hypoxia-independent stabilization of HIF-1α. Moreover, HIF-1α stabilization did not associate with oncogenic activation of BRAF or KRAS or Von Hippel-Lindau (VHL) mutation. Prevalent HIF-1α expression in SAC and its precursors support the importance of HIF-1α-mediated pathways for the serrated route of colorectal carcinogenesis.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Microvasos/patologia , Neovascularização Patológica/patologia , Adenocarcinoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/genética , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
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