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Modern Pathology : An Official Journal... Apr 2021Currently there is no highly specific and sensitive marker to identify breast cancer-the most common malignancy in women. Breast cancer can be categorized as estrogen... (Comparative Study)
Comparative Study
Currently there is no highly specific and sensitive marker to identify breast cancer-the most common malignancy in women. Breast cancer can be categorized as estrogen receptor (ER)/progesterone receptor (PR)-positive luminal, human epidermal growth factor receptor 2 (HER2)-positive, or triple-negative breast cancer (TNBC) types based on the expression of ER, PR, and HER2. Although GATA3 is the most widely used tumor marker at present to determine the breast origin, which has been shown to be an excellent marker for ER-positive and low-grade breast cancer, but it does not work well for TNBC with sensitivity as low as <20% in metaplastic breast carcinoma. In the current study, through TCGA data mining we identified trichorhinophalangeal syndrome type 1 (TRPS1) as a specific gene for breast carcinoma across 31 solid tumor types. Moreover, high mRNA level of TRPS1 was found in all four subtypes of breast carcinoma including ER/PR-positive luminal A and B types, HER2-positive type, and basal-type/TNBC. We then analyzed TRPS1 expression in 479 cases of various types of breast cancer using immunochemistry staining, and found that TRPS1 and GATA3 had comparable positive expression in ER-positive (98% vs. 95%) and HER2-positive (87% vs. 88%) breast carcinomas. However, TRPS1 which was highly expressed in TNBC, was significantly higher than GATA3 expression in metaplastic (86% vs. 21%) and nonmetaplastic (86% vs. 51%) TNBC. In addition, TRPS1 expression was evaluated in 1234 cases of solid tumor from different organs. In contrast to the high expression of GATA3 in urothelial carcinoma, TRPS1 showed no or little expression in urothelial carcinomas or in other tumor types including lung adenocarcinoma, pancreatic adenocarcinoma, colon and gastric adenocarcinoma, renal cell carcinoma, melanoma, and ovarian carcinoma. These findings suggest that TRPS1 is a highly sensitive and specific marker for breast carcinoma and can be used as a great diagnostic tool, especially for TNBC.
Topics: Biomarkers, Tumor; Carcinoma; Databases, Genetic; Female; GATA3 Transcription Factor; Humans; Immunohistochemistry; Predictive Value of Tests; Repressor Proteins; Reproducibility of Results; Tissue Array Analysis; Triple Negative Breast Neoplasms
PubMed: 33011748
DOI: 10.1038/s41379-020-00692-8 -
Pathologica Feb 2021Neuroendocrine neoplasms of the appendix, colon and rectum are classified according to the most recent WHO classification as neuroendocrine tumors (NET), neuroendocrine... (Review)
Review
Neuroendocrine neoplasms of the appendix, colon and rectum are classified according to the most recent WHO classification as neuroendocrine tumors (NET), neuroendocrine carcinomas (NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNENs). NECs and MiNENs are aggressive neoplasms requiring multimodal treatment strategies. By contrast, NETs are, in most cases, indolent lesions occurring as incidental findings in the appendix or as polyps in the rectum. While most appendiceal and rectal NETs are considered relatively non-aggressive neoplasms, a few cases, may show a more aggressive clinical course. Unfortunately, clinical/pathological characteristics to select patients at high risk of recurrence/metastases are poorly consolidated. Diagnosis is generally easy and supported by the combination of morphology and immunohistochemistry. Differential diagnostic problems are for NECs/MiNENs with poorly differentiated adenocarcinomas, when immunohistochemical neuroendocrine markers are not obviously positive, whereas for NETs they are represented by the rare appendiceal tubular and clear cell variants (which may be confused with non-neuroendocrine cancers) and rectal L-cell tumors which may be chromogranin negative and prostatic marker positive.
Topics: Appendix; Carcinoma, Neuroendocrine; Colon; Humans; Infant, Newborn; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Rectum
PubMed: 33686307
DOI: 10.32074/1591-951X-230 -
Gastroenterology Mar 2022Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine...
BACKGROUND & AIMS
Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis.
METHODS
SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed.
RESULTS
SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox mice and was reversed with Spd.
CONCLUSIONS
Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.
Topics: Adenomatous Polyposis Coli Protein; Animals; Azoxymethane; Carcinogenesis; Colitis; Colitis, Ulcerative; Colon; Colonic Neoplasms; Dextran Sulfate; Gastrointestinal Microbiome; Gene Expression Regulation; Humans; Intestinal Mucosa; Male; Mice; Oxidoreductases Acting on CH-NH Group Donors; Precancerous Conditions; Protective Factors; RNA, Messenger; Severity of Illness Index; Spermidine; Weight Loss; alpha-Defensins; Polyamine Oxidase
PubMed: 34767785
DOI: 10.1053/j.gastro.2021.11.005 -
Scientific Reports Nov 2022Methyl-CpG-binding protein 2(MeCP2) is an important epigenetic regulatory factor that promotes many tumor developments, such as liver cancer, breast cancer, and...
Methyl-CpG-binding protein 2(MeCP2) is an important epigenetic regulatory factor that promotes many tumor developments, such as liver cancer, breast cancer, and colorectal cancer. So far, no pan-cancer analysis has been reported. Therefore, this study aims to explore pan-cancer's prognostic value, immune infiltration pattern, and biological function. We used bioinformatics methods to analyze the expression and prognostic significance of MeCP2, and the relationship between MeCP2 and clinicopathological parameters, genetic variation, methylation, phosphorylation, immune cell infiltration, and biological function in pan-cancer from using a public database. The results showed that expression of MeCP2 was up-regulated in 8 cancers and down-regulated in 2 cancers, which was remarkably correlated with the prognosis, pathological stage, grade and subtype of cancers. The promoter methylation level of MeCP2 DNA was decreased in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), liver hepatocellular carcinoma (LIHC), prostate adenocarcinoma (PRAD), uterine corpus endometrial carcinoma (UCEC), testicular germ cell tumors (TGCT), and stomach adenocarcinoma (STAD);decreased phosphorylation of S25, S90, S92, S241, S286, S325 and S435 was found in MeCP2, such as UCEC, lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), colon adenocarcinoma (COAD), and kidney renal clear cell carcinoma (KIRC). Furthermore, MeCP2 expression was significantly associated with multiple immunomodulators and immune cell infiltration levels across most tumors. Therefore, our pan-cancer explored the prognostic markers and immunotherapeutic value of MeCP2 in different cancers.
Topics: Male; Humans; Prognosis; Methyl-CpG-Binding Protein 2; Adenocarcinoma; Computational Biology; Carcinoma, Transitional Cell; Colonic Neoplasms; Urinary Bladder Neoplasms; Carcinoma, Renal Cell; Breast Neoplasms; Kidney Neoplasms
PubMed: 36323715
DOI: 10.1038/s41598-022-21328-8 -
Gastroenterology Sep 2019Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome...
BACKGROUND & AIMS
Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis.
METHODS
Colon cancer was induced in mice with intestine-specific disruption of Ppara (Ppara), Ppara (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry.
RESULTS
Levels of Ppara messenger RNA were reduced in colon tumors from mice. Ppara mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from Ppara mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from Ppara mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues.
CONCLUSIONS
Loss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.
Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Case-Control Studies; Cell Cycle Proteins; Cell Transformation, Neoplastic; Colon; Colonic Neoplasms; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Databases, Genetic; Disease Models, Animal; Fenofibrate; Gene Expression Regulation, Neoplastic; Humans; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; PPAR alpha; Protein-Arginine N-Methyltransferases; Signal Transduction
PubMed: 31154022
DOI: 10.1053/j.gastro.2019.05.057 -
Gastroenterology Jun 2021Gut microbial dysbiosis has pivotal involvement in colorectal cancer (CRC). However, the intratumoral microbiota and its association with CRC progression remain elusive....
BACKGROUND & AIMS
Gut microbial dysbiosis has pivotal involvement in colorectal cancer (CRC). However, the intratumoral microbiota and its association with CRC progression remain elusive. We aimed to determine the microbial community architecture within a neoplasia (CRC or adenoma) and its contribution to colorectal carcinogenesis.
METHODS
We collected 436 tissue biopsies from patients with CRC (n = 36) or adenoma (n = 32) (2-6 biopsies from a neoplasia plus 2-5 biopsies from adjacent normal tissues per individual). Microbial profiling was performed using 16S ribosomal RNA gene sequencing with subsequent investigation of microbiota diversities and heterogeneity. The correlation between microbial dysbiosis and host genetic alterations (KRAS mutation and microsatellite instability) in all neoplasia biopsies was also analyzed.
RESULTS
We discovered that intra-neoplasia microbial communities are heterogeneous. Abundances of some CRC-associated pathobionts (eg, Fusobacterium, Bacteroides, Parvimonas, and Prevotella) were found to be highly varied within a single neoplasia. Correlation of such heterogeneity with CRC development revealed alterations in microbial communities involving microbes with high intra-neoplasia variation in abundance. Moreover, we found that the intra-neoplasia variation in abundance of individual microbes changed along the adenoma-carcinoma sequence. We further determined that there was a significant difference in intra-neoplasia microbiota between biopsies with and without KRAS mutation (P < .001) or microsatellite instability (P < .001), and illustrated the association of intratumoral microbial heterogeneity with genetic alteration.
CONCLUSIONS
We demonstrated that intra-neoplasia microbiota is heterogeneous and correlated with colorectal carcinogenesis. Our findings provide new insights on the contribution of gut microbiota heterogeneity to CRC progression.
Topics: Adenoma; Aged; Biopsy; Carcinogenesis; Colon; Colorectal Neoplasms; Female; Gastrointestinal Microbiome; Genetic Heterogeneity; Humans; Male; Microsatellite Instability; Middle Aged; Proto-Oncogene Proteins p21(ras); RNA, Ribosomal, 16S
PubMed: 33581124
DOI: 10.1053/j.gastro.2021.02.020 -
Molecular Therapy : the Journal of the... May 2023Ulcerative colitis (UC) is a chronic or relapsing inflammatory disease with limited therapeutic outcomes. Pterostilbene (PSB) is a polyphenol-based anti-oxidant that has...
Ulcerative colitis (UC) is a chronic or relapsing inflammatory disease with limited therapeutic outcomes. Pterostilbene (PSB) is a polyphenol-based anti-oxidant that has received extensive interest for its intrinsic anti-inflammatory and anti-oxidative activities. This work aims to develop a reactive oxygen species (ROS)-responsive, folic acid (FA)-functionalized nanoparticle (NP) for efficient PSB delivery to treat UC. The resulting PSB@NP-FA had a nano-scaled diameter of 231 nm and a spherical shape. With ROS-responsive release and ROS-scavenging properties, PSB@NP could effectively scavenge HO, thereby protecting cells from HO-induced oxidative damage. After FA modification, the resulting PSB@NP-FA could be internalized by RAW 264.7 and Colon-26 cells efficiently and preferentially localized to the inflamed colon. In dextran sulfate sodium (DSS)-induced colitis models, PSB@NP-FA showed a prominent ROS-scavenging capacity and anti-inflammatory activity, therefore relieving murine colitis effectively. Mechanism results suggested that PSB@NP-FA ameliorated colitis by regulating dendritic cells (DCs), promoting macrophage polarization, and regulating T cell infiltration. Both innate and adaptive immunity were involved. More importantly, the combination of the PSB and dexamethasone (DEX) enhanced the therapeutic efficacy of colitis. This ROS-responsive and ROS-scavenging nanocarrier represents an alternative therapeutic approach to UC. It can also be used as an enhancer for classic anti-inflammatory drugs.
Topics: Mice; Animals; Reactive Oxygen Species; Hydrogen Peroxide; Disease Models, Animal; Colitis; Colon; Colitis, Ulcerative; Adaptive Immunity; Anti-Inflammatory Agents; Dextran Sulfate
PubMed: 36855303
DOI: 10.1016/j.ymthe.2023.02.017 -
Medical Archives (Sarajevo, Bosnia and... Oct 2019Colorectal Cancer (CRC) is the third most common malignant disease and the fourth most common cause of death associated with malignancy. Adenocarcinomas account for 95%... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Colorectal Cancer (CRC) is the third most common malignant disease and the fourth most common cause of death associated with malignancy. Adenocarcinomas account for 95% of all cases of colon cancer. Treatment usually includes a surgical resection which is preceded or followed by chemotherapy and radiotherapy depending on the stage. There is constant interest in the microbiological ecosystem of the intestine, which is considered to be crucial for the onset and progression of the disease as well as the development of postoperative complications. Iatrogenic factors associated with the treatment of CRC may result in pronounced expression of virulence of the bacterial intestinal flora and fulminant inflammatory response of the host which ultimately leads to adverse treatment results. The modulation of intestinal microflora by probiotics seems to be an effective method of reducing complications in surgical patients. The question is whether ordering probiotics can lead to more favourable treatment outcomes for our patients who are operated due to colorectal adenocarcinoma, and whether this should become common practice.
AIM
To demonstrate the clinical significance of probiotic administration in patients treated for colorectal adenocarcinoma and the results compared with relevant studies.
PATIENTS AND METHODS
In a randomized controlled prospective study conducted at the Clinic of General and Abdominal Surgery of the UCCS in the period of 01 January 2017 until 31 December 2017, there were a total of 78 patients with colorectal adenocarcinoma. Patients were divided into two groups: a group treated with oral probiotics (n = 39) according to the 2x1 scheme starting from the third postoperative day lasting for the next thirty days, followed by 1x1 lasting for two weeks in each subsequent month to one year, and the control group (n = 39) which was not routinely treated with probiotics.
RESULTS
A statistically significant difference in the benefit of using probiotics was found during postoperative hospitalization and the occurrence of fatal outcome in the first six months. All complications were more present in the group of patients untreated with probiotic, with statistical significance shown only in the case of ileus. Probiotic has a statistically significant reduction in postoperative complications in the localization of tumours on the rectum -33.3% and the ascending colon -16.7%.
CONCLUSION
There is a significant benefit of administering probiotics in surgically treated patients for colorectal adenocarcinoma.
Topics: Abdominal Abscess; Adenocarcinoma; Anastomotic Leak; Bifidobacterium; Colectomy; Colon, Ascending; Colorectal Neoplasms; Humans; Ileus; Lactobacillus; Neoplasm Staging; Postoperative Care; Postoperative Complications; Probiotics; Rectal Neoplasms; Streptococcus thermophilus; Surgical Wound Infection
PubMed: 31819304
DOI: 10.5455/medarh.2019.73.316-320 -
Cells Dec 2022BRCAness refers to the damaged homologous recombination (HR) function due to the defects in HR-involved non- genes. BRCAness is the important marker for the use of...
BRCAness refers to the damaged homologous recombination (HR) function due to the defects in HR-involved non- genes. BRCAness is the important marker for the use of synthetic lethal-based PARP inhibitor therapy in breast and ovarian cancer treatment. The success provides an opportunity of applying PARP inhibitor therapy to treat other cancer types with BRCAness features. However, systematic knowledge is lack for BRCAness in different cancer types beyond breast and ovarian cancer. We performed a comprehensive characterization for 40 BRCAness-related genes in 33 cancer types with over 10,000 cancer cases, including pathogenic variation, homozygotic deletion, promoter hypermethylation, gene expression, and clinical correlation of BRCAness in each cancer type. Using / mutated breast and ovarian cancer as the control, we observed that BRCAness is widely present in multiple cancer types. Based on the sum of the BRCAneass features in each cancer type, we identified the following 21 cancer types as the potential targets for PARPi therapy: adrenocortical carcinoma, bladder urothelial carcinoma, brain lower grade glioma, colon adenocarcinoma, esophageal carcinoma, head and neck squamous carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, rectum adenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, uterine carcinosarcoma, and uterine corpus endometrial carcinoma.
Topics: Male; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Adenocarcinoma; Melanoma; Carcinoma, Transitional Cell; Pancreatic Neoplasms; Skin Neoplasms; Colonic Neoplasms; Urinary Bladder Neoplasms; Ovarian Neoplasms; Carcinoma, Hepatocellular; Liver Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 36497135
DOI: 10.3390/cells11233877 -
Gut Mar 2022In this study, we determined whether () infection dampens the efficacy of cancer immunotherapies.
OBJECTIVE
In this study, we determined whether () infection dampens the efficacy of cancer immunotherapies.
DESIGN
Using mouse models, we evaluated whether immune checkpoint inhibitors or vaccine-based immunotherapies are effective in reducing tumour volumes of -infected mice. In humans, we evaluated the correlation between seropositivity and the efficacy of the programmed cell death protein 1 (PD-1) blockade therapy in patients with non-small-cell lung cancer (NSCLC).
RESULTS
In mice engrafted with MC38 colon adenocarcinoma or B16-OVA melanoma cells, the tumour volumes of non-infected mice undergoing anticytotoxic T-lymphocyte-associated protein 4 and/or programmed death ligand 1 or anti-cancer vaccine treatments were significantly smaller than those of infected mice. We observed a decreased number and activation status of tumour-specific CD8 T cells in the tumours of infected mice treated with cancer immunotherapies independent of the gut microbiome composition. Additionally, by performing an in vitro co-culture assay, we observed that dendritic cells of infected mice promote lower tumour-specific CD8 T cell proliferation. We performed retrospective human clinical studies in two independent cohorts. In the Dijon cohort, seropositivity was found to be associated with a decreased NSCLC patient survival on anti-PD-1 therapy. The survival median for seropositive patients was 6.7 months compared with 15.4 months for seronegative patients (p=0.001). Additionally, in the Montreal cohort, seropositivity was found to be associated with an apparent decrease of NSCLC patient progression-free survival on anti-PD-1 therapy.
CONCLUSION
Our study unveils for the first time that the stomach microbiota affects the response to cancer immunotherapies and that serology would be a powerful tool to personalize cancer immunotherapy treatment.
Topics: Adenocarcinoma; Animals; Cancer Vaccines; Carcinoma, Non-Small-Cell Lung; Colonic Neoplasms; Disease Models, Animal; Female; Helicobacter Infections; Helicobacter pylori; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Retrospective Studies
PubMed: 34253574
DOI: 10.1136/gutjnl-2020-323392