Progression Of Epithelial Tumors Research Articles

A novel shark VNAR antibody-based immunotoxin targeting TROP-2 for cancer therapy

TROP-2, a tumor-associated antigen, has been implicated in the progression of various epithelial tumors. Due to its favorable expression profile, TROP-2 has emerged as a promising target for antibody–drug conjugates (ADCs) based anti-tumor therapies. Although ADCs have shown efficacy in cancer treatment, their application in solid tumors is hindered by their high molecular weight, poor tumor penetration, and release of cytotoxic molecules. Therefore, a recombinant immunotoxin was developed based on a shark-derived variable domain of immunoglobulin new antigen receptor (VNAR) antibody. VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability. In this study, a shark VNAR phage display library was created, leading to the identification of shark VNAR-5G8 that targets TROP-2. VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2. Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2. Subsequently, VNAR-5G8 was fused with a truncated form of Pseudomonas exotoxin (PE38) to create the recombinant immunotoxin (5G8-PE38), which exhibited significant anti-tumor activity in vitro and in vivo. Overall, this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy.

Sequencing Analysis of MUC6 and MUC16 Gene Fragments in Patients with Oropharyngeal Squamous Cell Carcinoma Reveals Novel Mutations: A Preliminary Study.

The growing incidence of oropharyngeal squamous cell carcinoma (OPSCC) calls for better understanding of the mutational landscape of such cases. Mucins (MUCs) are multifunctional glycoproteins expressed by the epithelial cells and may be associated with the epithelial tumour invasion and progression. The present study aimed at the analysis of the sequence of selected MUC6 and MUC16 gene fragments in the tumour, as well as the margin, samples obtained from 18 OPSCC patients. Possible associations between the detected mutations and the clinicopathological and demographic characteristics of the study group were analysed. Sanger sequencing and bioinformatic data analysis of the selected MUC6 and MUC16 cDNA fragments were performed. Our study found 13 and 3 mutations in MUC6 and MUC16, respectively. In particular, one novelty variant found that the MUC6 gene (chr11:1018257 A>T) was the most frequent across our cohort, in both the tumour and the margin samples, and was then classified as a high impact, stop-gain mutation. The current study found novel mutations in MUC6 and MUC16 providing new insight into the genetic alternation in mucin genes among the OPSCC patients. Further studies, including larger cohorts, are recommended to recognise the pattern in which the mutations affect oropharyngeal carcinogenesis.

Deciphering Stromal Changes between Metastatic and Non-metastatic Canine Mammary Carcinomas

Cancer-associated stroma (CAS) is widely recognized to influence development and progression of epithelial tumours including breast cancer. Canine mammary tumours (CMTs) such as simple canine mammary carcinomas represent valuable models for human breast cancer also with respect to stromal reprogramming. However, it remains unclear whether and how CAS changes in metastatic tumours compared to non-metastatic ones. To characterize stromal changes between metastatic and non-metastatic CMTs and identify potential drivers of tumour progression, we analysed CAS and matched normal stroma from 16 non-metastatic and 15 metastatic CMTs by RNA-sequencing of microdissected FFPE tissue. We identified 1438 differentially regulated genes between CAS and normal stroma, supporting previous results demonstrating stromal reprogramming in CMTs to be comparable with CAS in human breast cancer and validating deregulation of pathways and genes associated with CAS. Using primary human fibroblasts activated by treatment with TGFβ, we demonstrate some of the strongest expression changes to be conserved in fibroblasts across species. Furthermore, we identify 132 differentially expressed genes between CAS from metastatic and non-metastatic tumours, with strong changes in pathways including chemotaxis, regulation of apoptosis, immune response and TGFβ signalling and validate deregulation of several targets using RT-qPCR. Finally, we identify specific upregulation of COL6A5, F5, GALNT3, CIT and MMP11 in metastatic CAS, suggesting high stromal expression of these targets to be linked to malignancy and metastasis of CMTs. In summary, our data present a resource supporting further research into stromal changes of the mammary gland in relation to metastasis with implications for both canine and human mammary cancer.

088 Deciphering the molecular signals of EGFR pathway activation in Dlx3 deficient skin in cSCC

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. Emerging evidence suggests that homeoproteins can act as modulators of tumor initiation and progression in cSCC. DLX3 is a homeobox transcription factor which plays pivotal roles in embryonic development and epidermal homeostasis. Previous work from our lab, using both human samples and a Dlx3 knock-out (Dlx3cKO) mouse model, demonstrated DLX3’s tumor suppressive role in epithelial tumor development and tumor progression.

Pilot Investigation on p75ICD Expression in Laryngeal Squamous Cell Carcinoma.

Simple SummaryLaryngeal Squamous Cell Carcinoma (LSCC) is a squamous cancer with 2.4% new diagnoses each year, accounting for 25% of head and neck cancers, and has a high mortality rate. A deeper understanding of key mechanisms and knowledge of the putative target molecules of theranostic relevance are required. The receptor for neurotrophins p75NTR has been shown to be highly expressed in cancer stem cells (CSCs) of squamous epithelia, in LSCC as well as in other cancers. However, whether its cleavage product p75ICD expression, known to finely regulate the survival/death balance in neurons, is also a master regulator in cancer and LSCC in particular has not been directly addressed so far. To resolve this question, we performed a preliminary study using a limited number of LSCC specimens and studied p75ICD presence and expression pattern in LSCC specimens, showing that p75ICD may be a promising target in LSCC, requiring further investigation.We investigated the p75 Neurotrophin Receptor (p75NTR) expression and cleavage product p75NTR Intracellular Domain (p75ICD) as potential oncogenic and metastatic markers in human Laryngeal Squamous Cell Carcinoma (LSCC). p75NTR is highly expressed in Cancer Stem Cells (CSCs) of the laryngeal epithelia and it has been proposed as a marker for stemness, cell migration, and chemo-resistance in different squamous carcinomas. To investigate the clinical significance of p75NTR cleavage products in solid tumors, full-length and cleaved p75NTR expression was analyzed in laryngeal primary tumors from different-stage LSCC patients, diagnosed at the Policlinico Umberto I Hospital. Molecular and histological techniques were used to detect the expressions of p75NTR and p75ICD, and ATP Binding Cassette Subfamily G Member 2 (ABCG2), a CSC marker. We found regulated p75NTR cleavage during squamous epithelial tumor progression and tissue invasion. Our preliminary investigation suggests p75ICD expression and localization as possible features of tumorigenesis and metastaticity. Its co-localization with ABCG2 in squamous cells in the parenchyma invaded by the tumor formation allows us to hypothesize p75NTR and p75ICD roles in tumor invasion and CSC spreading in LSCC patients. These data might represent a starting point for a comprehensive analysis of p75NTR cleavage and of its clinical relevance as a potential molecular LSCC signature, possibly helping diagnosis, and improving prognosis and personalized therapy.

Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression

Colorectal cancers (CRCs) often display histological features indicative of aberrant differentiation but the molecular underpinnings of this trait and whether it directly drives disease progression is unclear. Here, we identify co-ordinate epigenetic inactivation of two epithelial-specific transcription factors, EHF and CDX1, as a mechanism driving differentiation loss in CRCs. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induced extensive chromatin remodelling, transcriptional re-programming, and differentiation along the enterocytic lineage, leading to reduced growth and metastasis. Strikingly, EHF and CDX1 were also able to reprogramme non-colonic epithelial cells to express colonic differentiation markers. By contrast, inactivation of EHF and CDX1 in well-differentiated CRC cells triggered tumour de-differentiation. Mechanistically, we demonstrate that EHF physically interacts with CDX1 via its PNT domain, and that these transcription factors co-operatively drive transcription of the colonic differentiation marker, VIL1. Compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupted normal colonic differentiation and significantly enhanced colorectal tumour progression. These findings thus reveal a novel mechanism driving epithelial de-differentiation and tumour progression in CRC.

Ets family proteins regulate the EMT transcription factors Snail and ZEB in cancer cells.

The epithelial–mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. Snail and ZEB1/2 (ZEB1 and ZEB2), known as EMT transcription factors, are key regulators of this transition. ZEB1/2 are positively correlated with EMT phenotypes and the aggressiveness of cancers. On the contrary, Snail is also correlated with the aggressiveness of cancers, but is not correlated with the expression of EMT marker proteins. Snail is induced by transforming growth factor‐β (TGF‐β), a well‐known inducer of EMT, in various cancer cells. Interestingly, Snail induction by TGF‐β is markedly enhanced by active Ras signals. Thus, cancer cells harboring an active Ras mutation exhibit a drastic induction of Snail by TGF‐β alone. Here, we found that members of the E26 transformation‐specific (Ets) transcription factor family, Ets1 and Ets2, contribute to the upregulation of both Snail and ZEB1/2. Snail induction by TGF‐β and active Ras is dramatically inhibited using siRNAs against both Ets1 and Ets2 together, but not on their own; in addition, siRNAs against both Ets1 and Ets2 also downregulate the constitutive expression of Snail and ZEB1/2 in cancer cells. Examination of several alternatively spliced variants of Ets1 revealed that p54‐Ets1, which includes exon VII, but not p42‐Ets1, which excludes exon VII, regulates the expression of the EMT transcription factors, suggesting that Ets1 is a crucial molecule for regulating Snail and ZEB1/2, and thus cancer progression is mediated through post‐translational modification of the exon VII domain.

Interrelationships between the extracellular matrix and the immune microenvironment that govern epithelial tumour progression.

Solid tumours are composed of cancer cells characterised by genetic mutations that underpin the disease, but also contain a suite of genetically normal cells and the extracellular matrix (ECM). These two latter components are constituents of the tumour microenvironment (TME), and are key determinants of tumour biology and thereby the outcomes for patients. The tumour ECM has been the subject of intense research over the past two decades, revealing key biochemical and mechanobiological principles that underpin its role in tumour cell proliferation and survival. However, the ECM also strongly influences the genetically normal immune cells within the microenvironment, regulating not only their proliferation and survival, but also their differentiation and access to tumour cells. Here we review recent advances in our knowledge of how the ECM regulates the tumour immune microenvironment and vice versa, comparing normal skin wound healing to the pathological condition of tumour progression.

HPV-Induced MiR-21 Promotes Epithelial Mesenchymal Transformation and Tumor Progression in Cervical Cancer Cells through the TGFβ R2/hTERC Pathway.

Cervical cancer (CC) is a common malignant tumor in women. It ranks first among the malignant tumors of woman reproductive organs and is one of the most important cancers in the world. Current studies suggest that human papillomavirus (HPV) infection, especially high-risk persistent infection, is the basic cause of cervical precancerous lesions and cervical cancer. MicroRNA-21 (miR-21) plays a role similar to oncogenes in the occurrence and growth of malignant tumors and can be developed as a potential target for treating malignant tumors. Recently, the study of the mechanism of malignant invasion and metastasis has made great progress. The current consensus is that the invasion and metastasis of malignant tumors is a complicated biological process with multistep and multigene control; the process of epithelial mesenchymal transition (EMT) may be the initial event of invasion and metastasis of epithelial malignant tumors. EMT means that epithelial cells obtain the characteristics of mesenchymal cells, which has main characteristics such as the loss of epithelial cell characteristics and the achievement of mesenchymal cell features, and then induce epithelial cells to acquire the ability of migration and invasion, and participate in many physiological and pathological processes of human body, including embryogenesis, organ differentiation, tissue inflammation, and wound healing. Research has proved that miR-21 is associated with the invasion and metastasis of cervical cancer, and its specific mechanism has not been completely clear; EMT exerts a significant effect on the invasion and metastasis of epithelial malignant tumors; we speculate whether miR-21 regulates the EMT process of cervical cancer cells. ELISA and RT-PCR studied HPV-induced cervical cancer cells, and it was found that HPV may induce miR-21 to pass through the TGF β R2/hTERC pathway which promotes epithelial stromal transformation and tumor progression of cervical cancer cells.

Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment.

Transforming Growth Factor-β (TGF-β) is a key regulator of embryonic development, adult tissue homeostasis, and lesion repair. In tumors, TGF-β is a potent inhibitor of early stage tumorigenesis and promotes late stage tumor progression and metastasis. Here, we review the roles of TGF-β as well as components of its signaling pathways in tumorigenesis. We will discuss how a core property of TGF-β, namely its ability to change cell differentiation, leads to the transition of epithelial cells, endothelial cells and fibroblasts to a myofibroblastoid phenotype, changes differentiation and polarization of immune cells, and induces metabolic reprogramming of cells, all of which contribute to the progression of epithelial tumors.

Nomogram predict relapse-free survival of patients with thymic epithelial tumors after surgery

BackgroundHematological indicators and clinical characteristics play an important role in the evaluation of the progression and prognosis of thymic epithelial tumors. Therefore, we aimed to combine these potential indicators to establish a prognostic nomogram to determine the relapse-free survival (RFS) of patients with thymic epithelial tumors undergoing thymectomy.MethodsThis retrospective study was conducted on 156 patients who underwent thymectomy between May 2004 and August 2015. Cox regression analysis were performed to determine the potential indicators related to prognosis and combine these indicators to create a nomogram for visual prediction. The prognostic predictive ability of the nomogram was evaluated using the consistency index (C-index), receiver operating characteristic (ROC) curve, and risk stratification. Decision curve analysis was used to evaluate the net benefits of the model.ResultsPreoperative albumin levels, neutrophil-to-lymphocyte ratio (NLR), T stage, and WHO histologic types were included in the nomogram. In the training cohort, the nomogram showed well prognostic ability (C index: 0.902). Calibration curves for the relapse-free survival (RFS) were in good agreement with the standard lines in training and validation cohorts.ConclusionsCombining clinical and hematologic factors, the nomogram performed well in predicting the prognosis and the relapse-free survival of this patient population. And it has potential to identify high-risk patients at an early stage. This is a relatively novel approach for the prediction of RFS in this patient population.

Downregulation of the FTO m6A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors.

Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N6-methyladenosine (m6A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m6A and altered 3'-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.

A mini-review regarding the carcinogenesis and morphology of serous tumors of the ovary, fallopian tube and peritoneum

Similar to the already well-recognized adenoma-carcinoma sequence in colorectal cancer pathogenesis, it has been believed for many decades that the progression of ovarian epithelial tumors occurs from benign serous cystadenomas to borderline tumors, to well-differentiated carcinomas, and ultimately, to poorly differentiated carcinomas. However, it is currently accepted that low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC) are fundamentally different tumor types and, consequently, different diseases. In fact, whereas the benign-borderline-malignant sequence seems to apply quite well to low-grade serous carcinoma, the sequence of genetic alterations in high-grade serous carcinoma is substantially different. In this mini-review, we included the current consensus regarding the morphological and etiopathogenic results regarding serous tumors of the ovary, fallopian tube and peritoneum. It also briefly describes the history of benign, borderline and malignant serous tumors, discussing multiple types of dichotomies in serous carcinomas of the female genital tract and summarizing the current molecular classification.

Abstract 1796: Requirement for LIM kinases in acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) is a highly aggressive disease which, in spite of extensive research in the last decades, is still treated with conventional chemotherapeutic regimens in most cases. Recent approvals of FLT3 and IDH1/2 inhibitors have highlighted the promise of targeted approaches for personalized AML therapy. However, the majority of AML driver mutations currently remain “undruggable”, making the search for additional molecular targets imperative. LIM kinases 1 and 2 (LIMK1/LIMK2), which are primarily known for regulating actin dynamics via phosphorylation of the actin-depolymerizing factor cofilin, have previously been implicated in progression and metastasis formation of several epithelial tumors. However, their function in leukemia, and AML in particular, has not been addressed in detail. Using high-throughput RNA interference (RNAi) screens in AML cell lines, we identified LIMK1 as a potential novel molecular target for AML treatment. High LIMK1 expression was significantly correlated with shorter survival of AML patients, and was associated with NPM1 and DNMT3A mutations, MLL rearrangements, and elevated HOX gene expression. RNAi- and CRISPR/Cas9-mediated suppression, as well as pharmacologic inhibition of LIMK1 and its close homolog LIMK2, reduced colony formation and decreased proliferation due to slowed cell cycle progression of MLL-rearranged AML cell lines and patient-derived xenograft samples. This was accompanied by morphologic changes indicative of myeloid differentiation. Transcriptome analysis showed upregulation of several tumor suppressors as well as downregulation of HOXA9 targets and mitosis-associated genes in response to LIMK1 suppression, providing a potential mechanistic explanation for the anti-leukemic phenotype. Finally, we observed a mutual regulation between LIMK1 and CDK6, a kinase known to be involved in the differentiation block of MLL-rearranged AML, and addition of the CDK6 inhibitor palbociclib further enhanced the anti-proliferative effect of LIMK1 depletion. Our data therefore suggest that LIM kinases are promising targets for AML therapy. Citation Format: Patrizia Jensen, Michela Carlet, Jana Kress, Andrea Weber, Ines Brunner, Mikolaj Slabicki, Gregor Grill, Simon Weisemann, Ya-Yun Cheng, Irmela Jeremias, Claudia Scholl, Stefan Fröhling. Requirement for LIM kinases in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1796.

A Genetic Analysis of Tumor Progression in Drosophila Identifies the Cohesin Complex as a Suppressor of Individual and Collective Cell Invasion.

SummaryMetastasis is the leading cause of death for patients with cancer. Consequently it is imperative that we improve our understanding of the molecular mechanisms that underlie progression of tumor growth toward malignancy. Advances in genome characterization technologies have been very successful in identifying commonly mutated or misregulated genes in a variety of human cancers. However, the difficulty in evaluating whether these candidates drive tumor progression remains a major challenge. Using the genetic amenability of Drosophila melanogaster we generated tumors with specific genotypes in the living animal and carried out a detailed systematic loss-of-function analysis to identify conserved genes that enhance or suppress epithelial tumor progression. This enabled the discovery of functional cooperative regulators of invasion and the establishment of a network of conserved invasion suppressors. This includes constituents of the cohesin complex, whose loss of function either promotes individual or collective cell invasion, depending on the severity of effect on cohesin complex function.

Interplay among SNAIL Transcription Factor, MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Regulation of Tumor Growth and Metastasis.

SNAIL (SNAI1) is a zinc finger transcription factor that binds to E-box sequences and regulates the expression of genes. It usually acts as a gene repressor, but it may also activate the expression of genes. SNAIL plays a key role in the regulation of epithelial to mesenchymal transition, which is the main mechanism responsible for the progression and metastasis of epithelial tumors. Nevertheless, it also regulates different processes that are responsible for tumor growth, such as the activity of cancer stem cells, the control of cell metabolism, and the regulation of differentiation. Different proteins and microRNAs may regulate the SNAIL level, and SNAIL may be an important regulator of microRNA expression as well. The interplay among SNAIL, microRNAs, long non-coding RNAs, and circular RNAs is a key event in the regulation of tumor growth and metastasis. This review for the first time discusses different types of regulation between SNAIL and non-coding RNAs with a focus on feedback loops and the role of competitive RNA. Understanding these mechanisms may help develop novel therapeutic strategies against cancer based on microRNAs.

Fibronectin and Periostin as Prognostic Markers in Ovarian Cancer

Previously, based on a DNA microarray experiment, we identified a 96-gene prognostic signature associated with the shorter survival of ovarian cancer patients. We hypothesized that some differentially expressed protein-coding genes from this signature could potentially serve as prognostic markers. The present study was aimed to validate two proteins, namely fibronectin (FN1) and periostin (POSTN), in the independent set of ovarian cancer samples. Both proteins are mainly known as extracellular matrix proteins with many important functions in physiology. However, there are also indications that they are implicated in cancer, including ovarian cancer. The expression of these proteins was immunohistochemically analyzed in 108 surgical samples of advanced ovarian cancer (majority: high-grade serous) and additionally on tissue arrays representing different stages of the progression of ovarian and fallopian tube epithelial tumors, from normal epithelia, through benign tumors, to adenocarcinomas of different stages. The correlation with clinical, pathological, and molecular features was evaluated. Kaplan–Meier survival analysis and Cox-proportional hazards models were used to estimate the correlation of the expression levels these proteins with survival. We observed that the higher expression of fibronectin in the tumor stroma was highly associated with shorter overall survival (OS) (Kaplan–Meier analysis, log-rank test p = 0.003). Periostin was also associated with shorter OS (p = 0.04). When we analyzed the combined score, calculated by adding together individual scores for stromal fibronectin and periostin expression, Cox regression demonstrated that this joint FN1&POSTN score was an independent prognostic factor for OS (HR = 2.16; 95% CI: 1.02–4.60; p = 0.044). The expression of fibronectin and periostin was also associated with the source of ovarian tumor sample: metastases showed higher expression of these proteins than primary tumor samples (χ2 test, p = 0.024 and p = 0.032). Elevated expression of fibronectin and periostin was also more common in fallopian cancers than in ovarian cancers. Our results support some previous observations that fibronectin and periostin have a prognostic significance in ovarian cancer. In addition, we propose the joint FN1&POSTN score as an independent prognostic factor for OS. Based on our results, it may also be speculated that these proteins are related to tumor progression and/or may indicate fallopian–epithelial origin of the tumor.

Mucosal-Associated Invariant T Cells in Tumors of Epithelial Origin.

Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes that circulate in blood and also reside in mucosal tissues. Blood MAIT cells are typically highly Th1-polarized, while those in mucosal tissues include both Th1- and Th17-polarized subsets. MAIT cells mount cytokine and cytolytic responses as a result of T cell receptor (TCR)-mediated recognition of microbially derived metabolites of riboflavin (vitamin B2) presented by the MR1 antigen-presenting molecule. Additionally, MAIT cells can be activated by inflammatory cytokines produced by antigen-presenting cells (APCs) that have been exposed to pathogen-associated molecular patterns (PAMPs). Since the antigenic metabolites of riboflavin recognized by MAIT cells are produced by many microorganisms, including pathogens as well as non-pathogenic colonists, the inflammatory state of the tissue may be a key feature that determines the nature of MAIT cell responses. Under normal conditions where inflammatory cytokines are not produced, MAIT cell responses to microbial metabolites may simply serve to help maintain a healthy balance between epithelial cells and microbial colonists. In contrast, in situations where inflammatory cytokines are produced (e.g., pathogenic infection or damage to epithelial tissue), MAIT cell responses may be more potently pro-inflammatory. Since chronic inflammation and microbial drivers are associated with tumorigenesis and also trigger MAIT cell responses, the nexus of MAIT cells, local microbiomes, and epithelial cells may play an important role in epithelial carcinogenesis. This chapter reviews current information about MAIT cells and epithelial tumors, where the balance of evidence suggests that enrichment of Th17-polarized MAIT cells at tumor sites associates with poor patient prognosis. Studying the role of MAIT cells and their interactions with resident microbes offers a novel view of the biology of epithelial tumor progression and may ultimately lead to new approaches to target MAIT cells clinically.

Low BCL9 expression inhibited ovarian epithelial malignant tumor progression by decreasing proliferation, migration, and increasing apoptosis to cancer cells

BackgroundAbnormal activation of the classic Wnt signaling pathway is closely related to the occurrence of epithelial cancers. B-cell lymphoma 9 (BCL9), a transcription factor, is a novel oncogene discovered in the classic Wnt pathway and promotes the occurrence and development of various tumors. Ovarian cancer is the gynecological malignant tumor with the highest mortality because it is difficult to diagnose early, and easy to relapse and metastasis. The expression and role of BCL9 in epithelial ovarian cancer (EOC) have not been studied. Thus, in this research, we aimed to investigate the expression and clinical significance of BCL9 in EOC tissues and its effect on the malignant biological behavior of human ovarian cancer cells.MethodsWe detect the expression of BCL9 in ovarian epithelial tumor tissues and normal ovarian tissues using immunohistochemistry and analyzed the relationship between it and clinicopathological parameters and patient prognosis. The expression of proteins was detected by Western blot. The MTT assay, flow cytometry, the scratch assay, and the transwell assay were used to detect cell proliferation, apoptosis, migration, and invasion, respectively. A total of 374 ovarian cancer tissue samples were collected using TCGA database. A gene set enrichment analysis of BCL9 was performed.ResultsBCL9 was overexpressed in EOC tissues. The level of BCL9 expression was correlated with the 5-year progression-free survival rate and overall survival rate in ovarian cancer patients and independently predicted the risk of ovarian cancer recurrence. Low BCL9 expression inhibited proliferation, invasion and migration of EOC cells, decreased MMP2 and MMP9 expression of ES-2 cell line, increased the BAX/BCL2 ratio and promoted apoptosis of EOC cells.ConclusionBCL9 is overexpressed in epithelial ovarian tumors, resulting in a poor prognosis for ovarian cancer patients. Low BCL9 expression can promote ovarian cancer cell apoptosis, inhibit proliferation and migration. BCL9 promotes the development of ovarian cancer.

Thyroid hormone induces progression and invasiveness of squamous cell carcinomas by promoting a ZEB-1/E-cadherin switch

Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses E-cadherin expression. Accordingly, in human SCC, elevated D2 (the T3-producing enzyme) correlates with tumor grade and is associated with an increased risk of postsurgical relapse and shorter disease-free survival. These data provide the first in vivo demonstration that TH and its activating enzyme, D2, play an effective role not only in the EMT but also in the entire neoplastic cascade starting from tumor formation up to metastatic transformation, and supports the concept that TH is an EMT promoter. Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH signaling may suppress the metastatic proclivity of SCC.