Histopathological atlas of desmoplastic reaction characterization in colorectal cancer.
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ABSTRACT:
SUBMITTER: Ueno H
PROVIDER: S-EPMC8193706 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this work, we reported a strategy to produce 3D in vitro microtissues of pancreatic ductal adenocarcinoma (PDAC) for studying the desmoplastic reaction activated by the stroma-cancer crosstalk. The purpose of this dataset was to examine the transcriptional expression changes of normal fibroblasts (NF), cancer-associated fibroblasts (CAF) and pancreatic adenocarcinoma cell line (PT45) in 3D versus 2D culture and in mono-culture versus co-culture. Illumina Human BeadChips were used to profile the transcriptome after 12 days of culture. We reported that human PDAC microtissues, obtained by co-culturing PT45 with NF or CAF within biodegradable microcarriers in spinner flask bioreactor, closely recapitulate key PDAC microenvironment characteristics.
2016-12-14 | GSE81850 | GEO
Project description:BackgroundExisting high-risk factors are insufficient to accurately predict the postoperative recurrence risk of stage II colorectal cancer (CRC). The discovery of additional prognostic markers may be the key to improving the current status of stage II CRC treatment. The present study aimed to evaluate the relationship among desmoplastic reaction (DR), tumor budding (TBd), the tumor-stroma ratio (TSR) and their prognostic value for relapse-free survival (RFS).MethodsIn this study, 207 patients with histologically confirmed stage II CRC from January 2012 to August 2018 were retrospectively reviewed from a single center; the cohort was divided into subgroups based on low or high TSR, and low, intermediate or high DR and TBd. Kaplan-Meier curve analysis and log-rank test were applied to examine RFS among subgroups. Univariate and multivariate Cox proportional hazards analyses were used to identify independent factors associated with RFS, and a nomogram was subsequently developed.ResultsAbnormal CA242, CEA, T4 stage, presence of hypertension, internal obstruction or perforation (IOP), lymphovascular or/and perineural invasion (PNI), number of nodes examined less than 12, low-frequency microsatellite instability (MSI-L), higher Ki-67 and immature DR were associated with a lower RFS. In multivariable analysis, DR (HR =2.111; 95% CI: 1.184-3.766; P=0.011), LVI (HR =1.919; 95% CI: 1.004-3.669; P=0.049) and PNI (HR =2.724; 95% CI: 1.362-5.448; P=0.005) were prognostic factors for RFS. On this basis, a nomogram that integrated DR and clinicopathologic predictors for predicting RFS passed the calibration and had an area under the curve of 0.826.ConclusionsThe prognostic significance of DR outperformed TBd and TSR, therefore, we recommend adding DR as a biomarker in routine pathological reports. The novel nomogram combining these factors may be used as a reliable and effective tool for the prediction of RFS in stage II CRC, thus helping optimize therapeutic regimens under cooperation of oncologists and surgeons. Further multicentric studies are required for validation of this novel, simple and cost-effective prognostic model.
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Project description:BackgroundIn patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy.MethodsAll consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver.ResultsIn total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n = 367), the dHGP was present in 19% (n = 68) and the non-dHGP was present in 81% (n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort (n = 365), more patients were found to express dHGP (n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen.ConclusionsThe current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials.
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Project description:Bone morphogenetic proteins (BMPs) are a group of growth factors with dual functions in cancer development and progression. Recently, certain tumor-promoting roles have been identified for selected antagonists/inhibitors (BMPIs) of this developmental pathway. A recent focus on the implication of BMP in colorectal cancer progression has emerged, mainly due to the presence of inactivating mutations in several members of the canonical signaling cascade. However, the detailed expression profiles of BMPIs remain largely unknown. Based on our previous work, whereby three specific BMPIs, gremlin-1 (GREM1), high-temperature requirement A3 (HTRA3) and follistatin (FST) were collectively overexpressed in desmoplastic cocultures of colorectal cancer (CRC), here, we undertook an immunohistochemical approach to describe the patterns of their expression in CRC patients. Two major characteristics described the BMPI expression signature: First, the synchronous and coordinated stromal and epithelial overexpression of individual BMPIs in desmoplastic lesions, which demonstrated that all three of them contribute to increasing levels of BMP antagonism in such areas. Second, the presence of microenvironmental polarity in the BMPI pattern of expression, which was indicated through the preferential expression of HTRA3 in the stromal, and the parallel FST/GREM1 expression in the epithelial component of the investigated sections. In addition, expression of HTRA3 in the epithelial compartment of the tumors demonstrated a significant predictive power to discriminate between tumor-budding-bearing and tumor-budding-free desmoplastic microenvironments. Together, these findings contribute to the understanding of signaling dynamics of BMP antagonism in the colorectal cancer desmoplastic invasion front.
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Project description:BackgroundDespite extensive research, the details of the biological mechanisms by which cancer cells acquire motility and invasiveness are largely unknown. This study identifies an invasion associated gene signature shedding light on these mechanisms.MethodsWe analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype, in this case high-stage cancer.ResultsWe conclude that there is one shared "core" metastasis-associated gene expression signature corresponding to a specific variant of stromal desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the corresponding biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. Therefore, its presence indicates that the corresponding stage has been reached. It has several features, such as coordinated overexpression of particular collagens, mainly COL11A1 and other genes, mainly THBS2 and INHBA. The composition of the overexpressed genes indicates invasion-facilitating altered proteolysis in the extracellular matrix. The prominent presence in the signature of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-β signaling, because activin A is a member of the TGF-β superfamily consisting of an INHBA homodimer. Furthermore, we establish that the signature is predictive of neoadjuvant therapy response in at least one breast cancer data set.ConclusionsTherefore, these results can be used for developing high specificity biomarkers sensing cancer invasion and predicting response to neoadjuvant therapy, as well as potential multi-cancer metastasis inhibiting therapeutics targeting the corresponding biological mechanism.
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Project description:AimsTumour budding (TB), desmoplastic reaction (DR) and intraepithelial tumour infiltrating lymphocytes (iTILs) are recently recognised prognostic factors in colorectal cancer (CRC). In this study, we evaluated their significance and relationship to each other and their cumulative effect on survival.Methods and resultsA total of 372 stages I-III CRC cases from 2013 to 2016 were included. Low TB was identified in 302 (81%) cases, immature/myxoid DR in 67 (18%) cases and iTILs in 130 (35.0%) cases. iTILs was associated with low budding (P = 0.0247), non-myxoid DR (P = 0.0004), poorly differentiated histology (P = 0.0015), absence of perineural invasion (P = 0.0367) and loss of mismatch repair proteins (P = 0.0002). Absence of iTILs and presence of immature/myxoid DR were associated with a worse recurrence-free survival (RFS) [hazard ratio (HR) = 2.191, 95% confidence interval (CI) = 1.232-3.895; and HR = 5.706, 95% CI = 3.632-8.964, respectively]. A competing risk analysis showed statistically significant prognostic groups combining iTILs and TB (P < 0.0001). Cases with iTILs and low TB were associated with better RFS compared to cases without iTILs and with intermediate/high TB (HR = 0.214, 95% CI = 0.109-0.421). Similarly, combining iTILs and DR revealed statistically significant prognostic groups (P < 0.0001). Cases with iTILs and a non-myxoid DR had better RFS compared to cases without iTILs and immature/myxoid DR (HR = 0.113, 95% CI = 0.056-0.230). On multivariate cause-specific analysis, patients' age (P = 0.0045), iTILs (P = 0.0345), DR (P < 0.0001) and pTNM prognostic groups (P < 0.0001) were associated with RFS.ConclusionsOur study validates the association of iTILs and DR as independent prognostic finding in CRC, and propose a prognostic model using the combinations of iTILs with TB and stromal reaction in CRC.
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Project description:The Cancer Genome Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor's genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two hundred and seven colorectal carcinomas that had undergone whole-exome sequencing as part of The Cancer Genome Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics constituted our study population. Upon analysis, a tight association between 'microsatellite instability-high histology' and microsatellite instability-high (P<0.001) was readily detected and helped validate our image-based histology evaluation. Further, we showed, (1) among all histologies, the not otherwise specified type had the lowest overall mutation count (P<0.001 for entire cohort, P<0.03 for the microsatellite-instable group), and among the microsatellite-instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (P<0.01); (2) cytosine phosphate guanine island methylator phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not otherwise specified; (3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming growth factor-β pathway when compared with non-mucinous histologies (P<0.001, P=0.01, and P<0.001, respectively); and (4) few colorectal cancers (<9%) exhibited upregulation of immune-inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite-instable (up to 43%, vs <3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth. These morphology-molecular associations are interesting and propose important clinical implications. The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies.
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Project description:AimThe aim of this study was to evaluate interobserver variability between individual pathologists and a panel of pathologists in the histopathological assessment of advanced colorectal neoplasms in the Dutch bowel cancer screening population.Methods and resultsHistological slides of adenomas with high-grade dysplasia and early colorectal carcinomas (CRC) from 20 different laboratories were reviewed by the pathology panel of the Dutch bowel screening programme. Interobserver variability was reported by descriptive statistics. In addition, potential clinical consequences of discrepancies were evaluated. A total of 104 cases of adenomas with high-grade dysplasia and 83 early CRCs were reviewed. Discrepancies were observed in 41 of 104 (39.4%) adenoma cases, which potentially had clinical consequences in 16 (15.4%) cases. For CRC, discrepancies were shown in 44 of 83 cases (53.0%) and would have potentially led to alternative treatment strategies in 25 (30.1%) cases. Most frequently, discrepancies were observed in the assessment of lymphovascular invasion (23 of 73 cases, 31.5%).ConclusionThis study showed that considerable interobserver variability is present in the histopathological assessment of advanced colorectal neoplasia, which may impact upon treatment choices. Additional stains and education, as well as intercollegial consultation, might decrease this variability.
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