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In most carcinomas, invasion of malignant cells into surrounding tissues involves their molecular reprogramming as part of an epithelial-to-mesenchymal transition (EMT). Mutation of the APC gene in most colorectal carcinomas (CRCs) contributes to the nuclear translocation of the oncoprotein β-catenin that upon binding to T-cell and lymphoid enhancer (TCF-LEF) factors triggers an EMT and a proinvasive gene expression profile. A key inducer of EMT is the ZEB1 transcription factor whose expression promotes tumorigenesis and metastasis in carcinomas. As inhibitor of the epithelial phenotype, ZEB1 is never present in the epithelium of normal colon or the tumor center of CRCs where β-catenin remains membranous. We show here that ZEB1 is expressed by epithelial cells in intestinal tumors from human patients (familial adenomatous polyposis) and mouse models (APCMin/+) with germline mutations of APC that result in nuclear accumulation of β-catenin. However, ZEB1 is not expressed in the epithelium of hereditary forms of CRCs that carry wild-type APC and where β-catenin is excluded from the nucleus (Lynch syndrome). We found that β-catenin/TCF4 binds directly to the ZEB1 promoter and activates its transcription. Knockdown of β-catenin and TCF4 in APC-mutated CRC cells inhibited endogenous ZEB1, whereas forced translocation of β-catenin to the nucleus in APC-wild-type CRC cells induced de novo expression of ZEB1. Upregulation of MT1-MMP and LAMC2 by β-catenin/TCF4 has been linked to invasiveness in CRCs, and we show here that both proteins are activated by ZEB1 coexpressing with it in primary colorectal tumors with mutated APC. These results set ZEB1 as an effector of β-catenin/TCF4 signaling in EMT and tumor progression.

Cancer is a complex multistep process involving genetic and epigenetic changes that eventually result in the activation of oncogenic pathways and/or inactivation of tumor suppressor signals. During cancer progression, cancer cells acquire a number of hallmarks that promote tumor growth and invasion. A crucial mechanism by which carcinoma cells enhance their invasive capacity is the dissolution of intercellular adhesions and the acquisition of a more motile mesenchymal phenotype as part of an epithelial-to-mesenchymal transition (EMT). Although many transcription factors can trigger it, the full molecular reprogramming occurring during an EMT is mainly orchestrated by three major groups of transcription factors: the ZEB, Snail and Twist families. Upregulated expression of these EMT-activating transcription factors (EMT-ATFs) promotes tumor invasiveness in cell lines and xenograft mice models and has been associated with poor clinical prognosis in human cancers. Evidence accumulated in the last few years indicates that EMT-ATFs also regulate an expanding set of cancer cell capabilities beyond tumor invasion. Thus, EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis. This article reviews the expanding portfolio of functions played by EMT-ATFs in cancer progression.

We developed a measurement setup and protocol reliably relating complex permittivity measurements with tissue characterization and specific histological features. We measured 148 fresh human tissue samples across 14 tissue types at 51 frequencies ranging from 200 MHz to 20 GHz, using an open-ended coaxial slim probe. Tissue samples were collected using a punch biopsy, ensuring that the sampled area encompassed the region where complex permittivity measurements were performed. This approach minimized experimental uncertainty related to potential position-dependent variations in permittivity. Once measured, the samples were then formalin-fixed and paraffin-embedded (FFPE) to obtain histological slides for microscopic analysis of tissue features. We observed that complex permittivity values are strongly associated with key histological features, including fat content, necrosis, and fibrosis. Most tissue samples exhibiting these features could be differentiated from nominal values for that tissue type, even accounting for statistical variability and instrumental uncertainties. These findings demonstrate the potential of incorporating fast in situ complex permittivity for fresh tissue characterization in pathology workflows. Furthermore, our work lays the groundwork for enhancing databases where complex permittivity values are measured under histological control, enabling precise correlations between permittivity values, tissue characterization, and histological features.

Development of robust prognostic and/or predictive biomarkers in patients with colorectal cancer (CRC) is imperative for advancing treatment strategies for this disease. We aimed to determine whether expression status of certain miRNAs might have prognostic/predictive value in CRC patients treated with conventional cytotoxic chemotherapies. We studied a cohort of 273 CRC specimens from stage II/III patients treated with 5-fluorouracil-based adjuvant chemotherapy and stage IV patients subjected to 5-fluorouracil and oxaliplatin-based chemotherapy. In a screening set (n = 44), 13 of 21 candidate miRNAs were successfully quantified by multiplex quantitative RT-PCR. In the validation set comprising of the entire patient cohort, miR-148a expression status was assessed by quantitative RT-PCR, and its promoter methylation was quantified by bisulfite pyrosequencing. Lastly, we analyzed the associations between miR-148a expression and patient survival. Among the candidate miRNAs studied, miR-148a expression was most significantly down-regulated in advanced CRC tissues. In stage III and IV CRC, low miR-148a expression was associated with significantly shorter disease free-survival (DFS), a worse therapeutic response, and poor overall survival (OS). Furthermore, miR-148a methylation status correlated inversely with its expression, and was associated with worse survival in stage IV CRC. In multivariate analysis, miR-148a expression was an independent prognostic/predictive biomarker for advanced CRC patients (DFS in stage III, low vs. high expression, HR 2.11; OS in stage IV, HR 1.93). MiR-148a status has a prognostic/predictive value in advanced CRC patients treated with conventional chemotherapy, which has important clinical implications in improving therapeutic strategies and personalized management of this malignancy.

Measurement of the component of fibrosis in Crohn's disease (CD) may have important therapeutic implications. The aim of this study was to characterize the Magnetic Resonance Imaging (MRI) findings that are differentially associated with the presence of fibrosis and those associated with inflammatory activity, using the pathological analysis of surgically resected intestinal lesions as reference standard. MRI studies with identical imaging protocol of 41 CD patients who underwent elective bowel resection within 4 months before surgery were reviewed. MRI evaluated wall thickening, edema, ulcers, signal intensity at submucosa at 70 s and 7 min after gadolinium injection, stenosis, and pattern of enhancement in each phase of the dynamic study and changes on this pattern over time. Pathological inflammatory and fibrosis scores were classified into three grades of severity. In all, 44 segments from 41 patients were analyzed. The pathological intensity of inflammation was associated with the following MRI parameters: hypersignal on T2 (P=0.02), mucosal enhancement (P=0.03), ulcerations (P=0.01), and blurred margins (P=0.05). The degree of fibrosis correlated with the percentage of enhancement gain (P<0.01), the pattern of enhancement at 7 min (P<0.01), and the presence of stenosis (P=0.05). Using percentage of enhancement gain, MRI is able to discriminate between mild-moderate and severe fibrosis deposition with a sensitivity of 0.94 and a specificity of 0.89. MRI is accurate for detecting the presence of severe fibrosis in CD lesions on the basis of the enhancement pattern.

Let-7 miRNAs comprise one of the largest and most highly expressed family of miRNAs among vertebrates, and is critical for promoting differentiation, regulating metabolism, inhibiting cellular proliferation, and repressing carcinogenesis in a variety of tissues. The large size of the Let-7 family of miRNAs has complicated the development of mutant animal models. Here we describe the comprehensive repression of all Let-7 miRNAs in the intestinal epithelium via low-level tissue-specific expression of the Lin28b RNA-binding protein and a conditional knockout of the MirLet7c-2/Mirlet7b locus. This ablation of Let-7 triggers the development of intestinal adenocarcinomas concomitant with reduced survival. Analysis of both mouse and human intestinal cancer specimens reveals that stem cell markers were significantly associated with loss of Let-7 miRNA expression, and that a number of Let-7 targets were elevated, including Hmga1 and Hmga2. Functional studies in 3-D enteroids revealed that Hmga2 is necessary and sufficient to mediate many characteristics of Let-7 depletion, namely accelerating cell cycle progression and enhancing a stem cell phenotype. In addition, inactivation of a single Hmga2 allele in the mouse intestine epithelium significantly represses tumorigenesis driven by Lin28b. In aggregate, we conclude that Let-7 depletion drives a stem cell phenotype and the development of intestinal cancer, primarily via Hmga2.

Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously. We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤ 50 years old (n=188), a group of sporadic CRC >50 years (MSS n=89; MSI n=46), and a group of Lynch syndrome CRCs (n=20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated. Mean LINE-1 methylation levels (± SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥ 65% LINE-1 methylation had significantly better overall survival (p=0.026, log rank test). LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.

Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.

A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. In hypoxic, Tgf-β1-rich interiors of adenomas, we show that adenoma cells divide asymmetrically to produce cancer-generating cells highlighted by epithelial mesenchymal transition and a CD44/Zeb1 loop. In these cells, Zeb1 represses the Smad inhibitor Zeb2/Sip1, causing Pten loss and launching Tgf-β1 signaling that drives nuclear translocation of Yap1. Surprisingly, the nuclear polarization of transcription factors during mitosis establishes parent and daughter fates prior to cytokinesis in sequential asymmetric divisions that generate cancer cells from precancerous lesions. Mutation or knockdown of Zeb1 in the lung blocked the production of CD44 hi , Zeb1 hi cancer-generating cells from adenoma cells. A CD44/Zeb1 loop then initiates two-step transition of precancerous cells to cancer cells via a stable intermediate population of cancer-generating cells. We show these initial cancer-generating cells are independent of cancer stem cells generated in tumors by p53-regulated reprogramming of existing cancer cells. Transition from premalignant lesion to cancer cell highlights tumor initiation. Here, the authors use a model of K-Ras-initiated lung cancer to document two successive asymmetric divisions, each driven by mitotic polarization of key transcription factors, which lead to generation of initial cancer cells.

Duodeno-duodenostomy (DD) has been proposed as a more physiological alternative to conventional duodeno-jejunostomy (DJ) for pancreas transplantation. Accessibility of percutaneous biopsies in these grafts has not yet been assessed. We conducted a retrospective study including all pancreatic percutaneous graft biopsies requested between November 2009 and July 2021. Whenever possible, biopsies were performed under ultrasound (US) guidance or computed tomography (CT) guidance when the US approach failed. Patients were classified into two groups according to surgical technique (DJ and DD). Accessibility, success for histological diagnosis and complications were compared. Biopsy was performed in 93/136 (68.4%) patients in the DJ group and 116/132 (87.9%) of the DD group ( p = 0.0001). The graft was not accessible for biopsy mainly due to intestinal loop interposition (n = 29 DJ, n = 10 DD). Adequate sample for histological diagnosis was obtained in 86/93 (92.5%) of the DJ group and 102/116 (87.9%) of the DD group ( p = 0.2777). One minor complication was noted in the DD group. The retrocolic position of the DD pancreatic graft does not limit access to percutaneous biopsy. This is a safe technique with a high histological diagnostic success rate.