Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion.
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ABSTRACT:
SUBMITTER: Singh P
PROVIDER: S-EPMC8042603 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The incidence of HPV-positive oropharyngeal cancer (HPV+?OPC) is increasing, thus presenting new challenges for disease detection and management. Noninvasive methods involving brush biopsies of diseased tissues were recently reported as insufficient for tumor detection in HPV+?OPC patients, likely due to differences between the site of tumor initiation at the base of involuted crypts and the site of brush biopsy at the crypt surface. We hypothesized that histologically normal surface epithelial cells in the oropharynx contain changes in nuclear morphology that arise due to tumor proximity. We analyzed the nuclear phenotype of matched tumor, tumor-adjacent normal, and contralateral normal tissues from biopsies of nine HPV+?OPC patients. Measurements of 89 nuclear features were used to train a random forest-based classifier to discriminate between normal and tumor nuclei. We then extracted voting scores from the trained classifier, which classify nuclei on a continuous scale from zero ("normal-like") to one ("tumor-like"). In each case, the average score of the adjacent normal nuclei was intermediate between the tumor and contralateral normal nuclei. These results provide evidence for the existence of phenotypic changes in histologically normal, tumor-adjacent surface epithelial cells, which could be used as brush biopsy-based biomarkers for HPV+?OPC detection.
| S-EPMC5866869 | biostudies-literature
Project description:This article contains further data and information from our published manuscript [1]. We aim to identify significant transcriptome alterations of total normal human thyroid vs. histologically normal thyroid adjacent to papillary thyroid carcinoma. We performed a systematic meta-analysis of all the available gene expression profiles for the whole organ also collecting gene expression data for the normal thyroid adjacent to papillary thyroid carcinoma. A differential quantitative transcriptome reference map was generated by using TRAM (Transcriptome Mapper) software able to combine, normalize and integrate a total of 35 datasets from total normal thyroid and 40 datasets from histologically normal thyroid adjacent to papillary thyroid carcinoma from different sources. This analysis identified genes and genome segments that significantly discriminated the two groups of samples. Differentially expressed genes were grouped and enrichment function analyses were performed identifying the main features of the differentially expressed genes between total normal thyroid and histologically normal thyroid adjacent to papillary thyroid carcinoma. The search for housekeeping genes retrieved 414 loci.
| S-EPMC6479735 | biostudies-literature
Project description:BackgroundThe expression of miRNA in head and neck squamous cell carcinomas (HNSCCs) that had been classified as high risk by surgical pathologic features and validated by trial outcome for disease recurrence was determined and compared with matched adjacent normal tissues.MethodsmiRNA and corresponding gene expression were determined using miRNA bioarrays and gene expression arrays.ResultsTwenty miRNAs were determined to be differentially regulated in the HNSCC samples when compared with their normal tissue counterparts. Quantitative reverse transcriptase-polymerase chain reaction confirmed differential regulation of miRNA expression, and gene expression analysis on these same-paired samples confirmed the loss of putative mRNA targets including genes such as adenomatous polyposis coli, programmed cell death protein 4, and TGF beta receptor 3 in the tumor samples.ConclusionsThese data suggest a role for the upregulation of specific miRNAs in high-risk HNSCC. Furthermore, upregulation of these miRNAs may be responsible for the elimination of mRNAs that lead to the growth and progression of HNSCC.
| S-EPMC2668741 | biostudies-literature
Project description:BackgroundThe molecular mechanisms involved in the invasion of bone by oral squamous cell carcinomas (OSCC) are poorly understood, and little is known about the role of cancer-associated fibroblasts (CAF), the presence of which confers a poor prognosis.MethodsClinicopathological data from 277 OSCC cases involving bone resections were reviewed, and 32 cases thoroughly analysed histologically. Immunohistochemistry was used to examine αSMA, RANKL and OPG. Western blotting and qPCR were used to assess myofibroblast (CAF-like) differentiation, RANKL and OPG expression in vitro, and RANKL secretion was analysed by ELISA. Osteoclastogenesis was examined using TRAP staining, multinucleation and pit forming assays.ResultsFibrous stroma intervened between tumour and bone in the majority of cases, with no direct contact between cancer cells and bone. RANKL and OPG, two proteins key to regulating bone resorption, were expressed in tumour cells as well as fibrous stroma adjacent to bone and αSMA-positive myofibroblastic CAF were consistently seen infiltrating into bone ahead of tumour cells. Human primary osteoblasts cultured with conditioned media from human OSCC-derived cells and human primary CAF showed a significant increase in RANKL and a decline in OPG mRNA expression. RANKL secretion was significantly increased in primary oral fibroblasts induced to differentiate into a CAF-like phenotype by transforming growth factor-β1 (TGF-β1) treatment and in primary CAF. Indirect co-culture of murine macrophages with conditioned media from CAF (experimentally derived and isolated from OSCCs) resulted in a marked increase in osteoclastogenesis (in excess of that provoked by cancer cells) determined by tartrate-resistant acid phosphatase activity, multinucleation and resorption pit formation.ConclusionsThis study is the first to describe a functional role for CAFs in bone invasion and turnover, identifying a novel potential therapeutic target and diagnostic indicator in this difficult to treat bone invasive malignancy.
| S-EPMC5589989 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (ESCC) is one of the 10 most incident cancer types in the world, and it is mainly associated with tobacco and alcohol consumption. ESCC mortality rates stand very close to its incidence, which is a direct consequence of a late diagnosis and an inefficient treatment. Although this scenery is quite alarming, the major molecular alterations that drive this carcinogenesis process remain unclear. We have previously shown through the first ESCC methylome analysis that TFF1 promoter is frequently hypermethylated in ESCC. Here, to evaluate TFF1 methylation as a potential biomarker of early ESCC diagnosis, we investigated the status of TFF1 promoter methylation and its expression in ESSC and histologically normal tumor surrounding tissue of ESCC patients in comparison to healthy esophagus of non-cancer individuals.Analysis of TFF1 promoter methylation, and gene and protein expression in 65 ESCC patients and 88 controls revealed that TFF1 methylation levels were already increased in histologically normal tumor surrounding tissue of ESCC patients when compared to healthy esophagus of non-cancer individuals. This increase in DNA methylation was followed by the reduction of TFF1 mRNA expression. Interestingly, TFF1 expression was capable of distinguishing tumor surrounding normal tissue from normal mucosa of healthy individuals with 92% accuracy. In addition, TFF1 protein was undetectable both in tumor and surrounding mucosa by immunohistochemistry, while submucosa glands of the healthy esophagus showed positive staining. Furthermore, treatment of TE-1 and TE-13 ESCC cell lines with decitabine led to a reduction of promoter methylation and consequent upregulation of TFF1 gene and protein expression. Finally, using TCGA data we showed that TFF1 loss is observed in ESCC, but not in esophageal adenocarcinoma, highlighting the different molecular mechanisms involved in the development of each histological subtype of esophageal cancer.This study shows that TFF1 expression is silenced in early phases of ESCC development, which seems to be mediated at least in part by promoter hypermethylation, and provides the basis for the use of TFF1 expression as a potential biomarker for early ESCC detection.
| S-EPMC5738900 | biostudies-other
Project description:BackgroundAdenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the most prevalent histological types among lung cancers. Distinguishing between these subtypes is critically important because they have different implications for prognosis and treatment. Normally, histopathological analyses are used to distinguish between the two, where the tissue samples are collected based on small endoscopic samples or needle aspirations. However, the lack of cell architecture in these small tissue samples hampers the process of distinguishing between the two subtypes. Molecular profiling can also be used to discriminate between the two lung cancer subtypes, on condition that the biopsy is composed of at least 50 % of tumor cells. However, for some cases, the tissue composition of a biopsy might be a mix of tumor and tumor-adjacent histologically normal tissue (TAHN). When this happens, a new biopsy is required, with associated cost, risks and discomfort to the patient. To avoid this problem, we hypothesize that a computational method can distinguish between lung cancer subtypes given tumor and TAHN tissue.MethodsUsing publicly available datasets for gene expression and DNA methylation, we applied four classification tasks, depending on the possible combinations of tumor and TAHN tissue. First, we used a feature selector (ReliefF/Limma) to select relevant variables, which were then used to build a simple naïve Bayes classification model. Then, we evaluated the classification performance of our models by measuring the area under the receiver operating characteristic curve (AUC). Finally, we analyzed the relevance of the selected genes using hierarchical clustering and IPA® software for gene functional analysis.ResultsAll Bayesian models achieved high classification performance (AUC > 0.94), which were confirmed by hierarchical cluster analysis. From the genes selected, 25 (93 %) were found to be related to cancer (19 were associated with ADC or SCC), confirming the biological relevance of our method.ConclusionsThe results from this study confirm that computational methods using tumor and TAHN tissue can serve as a prognostic tool for lung cancer subtype classification. Our study complements results from other studies where TAHN tissue has been used as prognostic tool for prostate cancer. The clinical implications of this finding could greatly benefit lung cancer patients.
| S-EPMC4778315 | biostudies-literature
Project description:Gene expression in histologically normal epithelium from breast cancer patients and cancer-free prophylactic mastectomy patients share a similar profile Introduction: We hypothesized that gene expression in histologically normal epithelium (NlEpi) would differ in breast cancer patients (HN) compared to usual-risk controls undergoing reduction mammoplasty (RM), and that gene expression in NlEpi from cancer-free prophylactic mastectomies from high-risk women (PM), would resemble HN gene expression. Methods: We analyzed gene expression in 73 NlEpi samples microdissected from frozen tissue. In 42 cases, we used Affymetrix HU133A microarrays to compare gene expression in 18 RM vs 18 age-matched HN (9 ER+, 9 ER-) and 6 PM. Data were validated with qPCR in 31 independent NlEpi samples (8 RM, 17 HN, 6 PM). Results: 98 probesets (86 genes) were differentially expressed between RM and HN samples. Perfoming supervised hierarchical analysis with these 98 probesets, PM and HN samples clustered together, away from RM samples. qPCR validation of independent samples was high (84%) and uniform in RM vs HN, and lower (58%), but more heterogeneous, in RM vs PM. The 86 genes were implicated in many processes including transcription and the MAPK pathway. Conclusion: Gene expression differs between NlEpi of cancer cases and controls. The cancer cases' profile can be discerned in high-risk NlEpi. This suggests that the profile is not an effect of the tumor, but may mark increased risk and reveal breast cancer's earliest genomic changes. We determined that 98 probesets significantly differed between reduction mammoplasty and histologically normal epithelium from breast cancer patients. We also found that the histologically normal epithelium from prophylactic mastectomy patients' gene expression was more similar to histologically normal epithelium from breast cancer patients' than to reduction mammoplasty patients' gene expression. These results demonstrate that gene expression differs between NlEpi of cancer cases and controls. The cancer cases’ profile can be discerned in high-risk NlEpi. This suggests that the profile is not an effect of the tumor, but may mark increased risk and reveal breast cancer's earliest genomic changes. 42 total laser capture microdissected histologically normal breast tissue samples were analyzed with Affymetrix HU133A microarrays. 36 samples were age-matched between reduction mammoplasty (n=18) and histologically normal epithelial samples from breast cancer patients (n=18; 9ER+, 9ER-). 6 histologically normal epithelial samples from prophylactic mastectomy patients were then compared to data generated from the original 36 sample comparison. Sample numbers correspond to individual patient samples.
| S-ECPF-GEOD-20437 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-09-10 | GSE157808 | GEO
Project description:Tumor-adjacent noncancerous tissues often exhibited abnormalities on molecular levels, which is described as field effect of cancerization. Accumulated evidence demonstrated that filed effect may also play important role in cancer progression. In the present study, we found that the gene expression profile in noncancerous lung tissues adjacent to lung squamous cell carcinoma (SCC) was significantly associated with regional lymph node status of patients. Significance Analysis of Microarrays (SAM) showed that 121 genes were significantly associated with lymph node metastasis (delta=0.75, FDR=0.069). Interestingly, all of the significant genes were up-regulated in the lymph node positive samples. For these genes, the most significant biological GO terms were extracellular structure organization, cell adhesion, regulation of cell motion/migration, and vessel development, etc, which were also involved in EMT process supported by another experiment in vitro. Tumor-adjacent histologically normal lung tissues were collected from 60 primary lung SCC patients, of whom 34 (56.7%) suffered regional lymph node metastasis. Gene expression profiling analysis of these samples was performed using Agilent 4x44K human whole genome gene expression microarray (G4112F).
| S-ECPF-GEOD-40588 | biostudies-other
Project description:BackgroundThe overall survival for patients with squamous cell carcinoma of the tongue is low and the search for early diagnostic and prognostic markers is thus essential. MicroRNAs have been suggested as potential prognostic and diagnostic candidates in squamous cell carcinoma of head and neck in general.MethodsOn the basis of the known differences between sub-sites within the oral cavity, we investigated the expression and role of microRNA-424 in squamous cell carcinoma arising in tongue. MicroRNA levels were measured by qRT-PCR in both tissue and plasma samples.ResultsLevels of microRNA-424 were upregulated in tongue squamous cell carcinoma, but not in tumours originating from gingiva or floor of the mouth. Interestingly, microRNA-424 was downregulated in clinically normal tongue tissue next to tumour compared with completely healthy tongue, indicating that microRNA-424 could be a marker of field cancerisation in this tumour type. However, expression of microRNA-424 in a tongue-derived epithelial cell line revealed no significant changes in the expression profile of proteins and genes.ConclusionsOur patient data show that microRNA-424 alterations are a marker of field cancerisation specific for tongue tumourigenesis, which also could have a role in development of tongue squamous cell carcinoma.
| S-EPMC4647232 | biostudies-literature