Expression of Trefoil Factor 1 (TFF1) in Cancer: A Tissue Microarray Study Involving 18,878 Tumors.

Background/Objectives: Trefoil factor 1 (TFF1) plays a role in the mucus barrier. Methods: To evaluate the prevalence of TFF1 expression in cancer, a tissue microarray containing 18,878 samples from 149 tumor types and 608 samples of 76 normal tissue types was analyzed through immunohistochemistry (IHC). Results: TFF1 staining was detectable in 65 of 149 tumor categories. The highest rates of TFF1 positivity were found in mucinous ovarian carcinomas (76.2%), colorectal adenomas and adenocarcinomas (47.1-75%), breast neoplasms (up to 72.9%), bilio-pancreatic adenocarcinomas (42.1-62.5%), gastro-esophageal adenocarcinomas (40.4-50.0%), neuroendocrine neoplasms (up to 45.5%), cervical adenocarcinomas (39.1%), and urothelial neoplasms (up to 24.3%). High TFF1 expression was related to a low grade of malignancy in non-invasive urothelial carcinomas of the bladder (p = 0.0225), low grade of malignancy (p = 0.0003), estrogen and progesterone receptor expression (p < 0.0001), non-triple negativity (p = 0.0005) in invasive breast cancer of no special type, and right-sided tumor location (p = 0.0021) in colorectal adenocarcinomas. Conclusions: TFF1 IHC has only limited utility for the discrimination of different tumor entities given its expression in many tumor entities. The link between TFF1 expression and parameters of malignancy argues for a relevant biological role of TFF1 in cancer. TFF1 may represent a suitable therapeutic target due to its expression in only a few normal cell types.

Oxidative State in Cutaneous Melanoma Progression: A Question of Balance.

Reactive oxygen species (ROS) are highly bioactive molecules involved not only in tissue physiology but also in the development of different human conditions, including premature aging, cardiovascular pathologies, neurological and neurodegenerative disorders, inflammatory diseases, and cancer. Among the different human tumors, cutaneous melanoma, the most aggressive and lethal form of skin cancer, is undoubtedly one of the most well-known "ROS-driven tumor", of which one of the main causes is represented by ultraviolet (UV) rays' exposure. Although the role of excessive ROS production in melanoma development in pro-tumorigenic cell fate is now well established, little is known about its contribution to the progression of the melanoma metastatic process. Increasing evidence suggests a dual role of ROS in melanoma progression: excessive ROS production may enhance cellular growth and promote therapeutic resistance, but at the same time, it can also have cytotoxic effects on cancer cells, inducing their apoptosis. In this context, the aim of the present work was to focus on the relationship between cell redox state and the signaling pathways directly involved in the metastatic processes. In addition, oxidative or antioxidant therapeutic strategies for metastatic melanoma were also reviewed and discussed.

Epigenetic regulation of HERVs: Implications for cancer immunotherapy.

BACKGROUND: Human endogenous retroviruses (HERVs), integrated into the human genome during primate evolution, constitute approximately 8% of the human genome. Although most HERVs are non-protein-coding owing to mutations, insertions, deletions, and truncations, recent research has revealed their diverse roles in biological processes, including disease pathogenesis. OBJECTIVE: Although many HERVs remain inactive, they have been implicated in various diseases, particularly cancer, prompting an increased interest in harnessing HERVs for therapeutic purposes. This review explores the recent advancements in our understanding of the biological roles of HERVs, emphasizing their clinical relevance in cancer treatment. METHODS: Here, we discuss how the detection of transposable elements (TEs), including HERVs, by the immune system triggers innate immune responses in human cancers. CONCLUSION: Additionally, we outline recent progress in elucidating the implications of HERV activation in cancer and how targeting HERVs holds promise for anti-cancer treatments by modulating epigenetic plasticity and disrupting cancer initiation and progression.

Reprogramming of glucose metabolism: The hallmark of malignant transformation and target for advanced diagnostics and treatments.

Reprogramming of cancer metabolism has become increasingly concerned over the last decade, particularly the reprogramming of glucose metabolism, also known as the "Warburg effect". The reprogramming of glucose metabolism is considered a novel hallmark of human cancers. A growing number of studies have shown that reprogramming of glucose metabolism can regulate many biological processes of cancers, including carcinogenesis, progression, metastasis, and drug resistance. In this review, we summarize the major biological functions, clinical significance, potential targets and signaling pathways of glucose metabolic reprogramming in human cancers. Moreover, the applications of natural products and small molecule inhibitors targeting glucose metabolic reprogramming are analyzed, some clinical agents targeting glucose metabolic reprogramming and trial statuses are summarized, as well as the pros and cons of targeting glucose metabolic reprogramming for cancer therapy are analyzed. Overall, the reprogramming of glucose metabolism plays an important role in the prediction, prevention, diagnosis and treatment of human cancers. Glucose metabolic reprogramming-related targets have great potential to serve as biomarkers for improving individual outcomes and prognosis in cancer patients. The clinical innovations related to targeting the reprogramming of glucose metabolism will be a hotspot for cancer therapy research in the future. We suggest that more high-quality clinical trials with more abundant drug formulations and toxicology experiments would be beneficial for the development and clinical application of drugs targeting reprogramming of glucose metabolism.This review will provide the researchers with the broader perspective and comprehensive understanding about the important significance of glucose metabolic reprogramming in human cancers.

Ataxia-Telangiectasia Mutated (ATM) gene signaling pathways in human cancers and their therapeutic implications.

Cancer is a multifaceted disease driven by abnormal cell growth and poses a significant global health threat. The multifactorial causes, differences in individual susceptibility to therapeutic drugs, and induced drug resistance pose major challenges in addressing cancers effectively. One of the most important aspects in making cancers highly heterogeneous in their physiology lies in the genes involved and the changes occurring to some of these genes in malignant conditions. The Genetic factors have been implicated in the oncogenesis, progression, responses to treatment, and metastasis. One such gene that plays a key role in human cancers is the mutated form of the Ataxia-telangiectasia gene (ATM). ATM gene located on chromosome 11q23, plays a vital role in maintaining genomic stability. Understanding the genetic basis of A-T is crucial for diagnosis, management, and treatment. Breast cancer, lung cancer, prostate cancer, and gastric cancer exhibit varying relationships with the ATM gene and influence their pathways. Targeting the ATM pathway proves promising for enhancing treatment effectiveness, especially in conjunction with DNA damage response pathways. Analyzing the therapeutic consequences of ATM mutations, especially in these cancer types facilitates the approaches for early detection, intervention, development of personalized treatment approaches, and improved patient outcomes. This review emphasizes the role of the ATM gene in various cancers, highlighting its impact on DNA repair pathways and therapeutic responses.

MicroRNA-98: the multifaceted regulator in human cancer progression and therapy.

MicroRNA-98 (miR-98) stands as an important molecule in the intricate landscape of oncology. As a subset of microRNAs, these small non-coding RNAs have accompanied a new era in cancer research, underpinning their significant roles in tumorigenesis, metastasis, and therapeutic interventions. This review provides a comprehensive insight into the biogenesis, molecular properties, and physiological undertakings of miR-98, highlighting its double-edged role in cancer progression-acting both as a tumor promoter and suppressor. Intriguingly, miR-98 has profound implications for various aspects of cancer progression, modulating key cellular functions, including proliferation, apoptosis, and the cell cycle. Given its expression patterns, the potential of miR-98 as a diagnostic and prognostic biomarker, especially in liquid biopsies and tumor tissues, is explored, emphasizing the hurdles in translating these findings clinically. The review concludes by evaluating therapeutic avenues to modulate miR-98 expression, addressing the challenges in therapy resistance, and assessing the efficacy of miR-98 interventions. In conclusion, while miR-98's involvement in cancer showcases promising diagnostic and therapeutic avenues, future research should pivot towards understanding its role in tumor-stroma interactions, immune modulation, and metabolic regulation, thereby unlocking novel strategies for cancer management.

c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy.

BACKGROUND: c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS: The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS: The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.

CDK16 as a potential prognostic biomarker correlated with an immunosuppressive tumor microenvironment and benefits in enhancing the effectiveness of immunotherapy in human cancers.

BACKGROUND: Cyclin-Dependent Kinase 16 (CDK16) plays significant biological roles in various diseases. Nonetheless, its function in different cancer types and its relationship with the Tumor Immune Microenvironment (TIME) are still not well-understood. METHODS: We analyzed the expression profile, genetic alterations, clinical features, and prognostic value of CDK16 in pan-cancer using data from The Cancer Genome Atlas, Genotype-Tissue Expression databases, and in vitro experiments. Additionally, the TIMER2 and ImmuCellAI databases were utilized to assess the correlation between CDK16 expression and immune cell infiltration levels. Finally, we examined the correlation between CDK16 and the response to immunotherapy using collected immunotherapy data. RESULTS: CDK16 is notably overexpressed in pan-cancer and is a risk factor for poor prognosis in various cancers. Our findings reveal that CDK16 regulates not only cell cycle-related functions to promote cell proliferation but also the autoimmunity-related functions of the innate and adaptive immune systems, along with other immune-related signaling pathways. Moreover, CDK16 overexpression contributes to an immunosuppressive tumor microenvironment, extensively suppressing immune-related features such as the expression of immune-related genes and pathways, as well as the count of immune-infiltrating cells. Our analysis indicated that individuals with low CDK16 expression showed higher response rates to immune checkpoint inhibitors and longer overall survival compared to those with high CDK16 expression. CONCLUSIONS: This study establishes CDK16 as a potential biomarker for predicting poor prognosis in a wide range of cancers. Its role in shaping the immunosuppressive tumor microenvironment and influencing the efficacy of immunotherapy highlights the urgent need for developing targeted therapies against CDK16, offering new avenues for cancer treatment and management.

Prostein expression in human tumors: a tissue microarray study on 19,202 tumors from 152 different Tumor entities.

BACKGROUND: Prostein (P501S), also termed solute carrier family 45 member 3 (SLC45A3) is an androgen regulated protein which is preferentially expressed in prostate epithelial cells. Because of its frequent expression in prostate cancer, prostein was suggested a diagnostic prostate cancer marker. METHODS: In order to comprehensively assess the diagnostic utility of prostein immunohistochemistry, a tissue microarray containing 19,202 samples from 152 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. RESULTS: Prostein immunostaining was typically cytoplasmic, granular and perinuclear. Prostein positivity was seen in 96.7% of 419 prostate cancers including 78.3% with strong staining. In 16,709 extra-prostatic tumors, prostein positivity was observed in 7.2% of all cases but only 0.3% had a strong staining. Overall, 50 different extra-prostatic tumor categories were prostein positive, 12 of which included at least one strongly positive case. Extra-prostatic tumors with highest rates of prostein positivity included different subtypes of salivary gland tumors (7.6-44.4%), neuroendocrine neoplasms (15.8-44.4%), adenocarcinomas of the gastrointestinal tract (7.3-14.8%), biliopancreatic adenocarcinomas (3.6-38.7%), hepatocellular carcinomas (8.1%), and adenocarcinomas of other organs (up to 21%). CONCLUSIONS: Our data provide a comprehensive overview on prostein expression in human cancers. Prostein is a highly sensitive prostate cancer marker occurring in > 96% of prostate cancers. Because prostein can also be expressed in various other tumor entities, classifying of a tumor mass as a prostate cancer should not be based on prostein positivity alone.

Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives.

Toll-like receptors (TLRs) serve as the body's first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries.

HGH1 and the immune landscape: a novel prognostic marker for immune-desert tumor microenvironment identification and immunotherapy outcome prediction in human cancers.

HGH1 homolog, a protein-coding gene, plays a crucial role in human growth and development. However, its role in human cancer remains unclear. For the first time, this study comprehensively evaluated the potential involvement of HGH1 in cancer prognosis and immunological function. To achieve this, data from various databases, including The Cancer Genome Atlas, Genotype Tissue Expression, Cancer Cell Lineage Encyclopedia, Human Protein Atlas, cBioPortal, Tumor Immune Estimation Resource and Immune Cell Abundance Identifier, were collated, as well as from one large clinical study, three immunotherapy cohorts and in vitro experiments. This study aims to elucidate the role of HGH1 expression in cancer prognosis and immune response. Our findings revealed a significant association between increased HGH1 expression and a worse prognosis across various cancer types. Predominantly, copy number variations were identified as the most common genetic mutations. Additionally, HGH1 was observed to not only regulate cell cycle-related functions to promote cell proliferation but also influence autoimmunity-related functions within both the innate and adaptive immune systems, along with other relevant immune-related signaling pathways. Gene set enrichment analysis and gene set variation analysis were used to substantiate these findings. HGH1 overexpression contributed to an immune-deficient (immune-desert) tumor microenvironment, which was characterized by a significant expression of immune-related features such as immune-related gene and pathway expression and the number of immune-infiltrating cells. Furthermore, the correlation between HGH1 expression and tumor mutational burden in four cancers and microsatellite instability in eight cancers was observed. This suggests that HGH1 has potential as an immunotherapeutic target. Immunotherapy data analysis supports this notion, demonstrating that patients with low HGH1 expression treated with immune checkpoint inhibitors exhibit improved survival rates and a higher likelihood of responding to immunotherapy than patients with high HGH1 expression. Collectively, these findings highlight the significant role of HGH1 in human cancers, illuminating its involvement in tumorigenesis and cancer immunity. Elevated HGH1 expression was identified to be indicative of an immune-desert tumor microenvironment. Consequently, the targeting of HGH1, particularly in combination with immune checkpoint inhibitor therapy, holds promise for enhancing therapeutic outcomes in patients with cancer.

Signal sequence receptor subunit 3: A novel indicator of immunosuppressive tumor microenvironment and clinical benefits from immunotherapy.

BACKGROUND: Signal sequence receptor subunit 3 (SSR3), a translocation-associated protein complex, plays a vital role in various diseases. However, its involvement in human cancers remains unclear. METHODS: We conducted a comprehensive analysis by integrating data from multiple sources, including the Cancer Genome Atlas, Cancer Cell Lineage Encyclopedia, Genotype Tissue Expression, Human Protein Atlas, cBioPortal, TIMER, and ImmuCellAI. Additionally, we incorporated data from a clinical trial, two immunotherapy cohorts, and in vitro experiments to investigate SSR3's impact on cancer prognosis and immune response. RESULTS: Our findings revealed a significant correlation between elevated SSR3 expression and unfavorable prognosis across various cancer types. Amplification is the most common genetic alteration in SSR3. Furthermore, functional enrichment analysis highlighted SSR3's regulatory role in promoting proliferation. In addition, SSR3 also serves as a pivotal mediator bridging the innate and adaptive immune systems and several related signaling pathways. Moreover, the correlation of SSR3 expression with tumor mutation burden in five cancer types, as well as with microsatellite instability in nine cancer types, suggests the potential of SSR3 as a predictive marker for immunotherapy response. To validate this hypothesis, we examined data from patients who underwent immunotherapy treatment. Our analysis revealed that individuals with low SSR3 expression demonstrated higher response rates to immune checkpoint inhibitors and longer overall survival compared to those with high SSR3 expression. CONCLUSIONS: Our study identifies SSR3 as a potential oncogene in humans, implicated in both tumorigenesis and cancer immunity. Elevated SSR3 expression is indicative of an immunosuppressive tumor microenvironment. Therefore, SSR3 holds promise as a potential prognostic biomarker and a target for immunotherapy in cancer treatment.

Icariin as a potential anticancer agent: a review of its biological effects on various cancers.

Numerous chemical compounds used in cancer treatment have been isolated from natural herbs to address the ever-increasing cancer incidence worldwide. Therein is icariin, which has been extensively studied for its therapeutic potential due to its anti-inflammatory, antioxidant, antidepressant, and aphrodisiac properties. However, there is a lack of comprehensive and detailed review of studies on icariin in cancer treatment. Given this, this study reviews and examines the relevant literature on the chemopreventive and therapeutic potentials of icariin in cancer treatment and describes its mechanism of action. The review shows that icariin has the property of inhibiting cancer progression and reversing drug resistance. Therefore, icariin may be a valuable potential agent for the prevention and treatment of various cancers due to its natural origin, safety, and low cost compared to conventional anticancer drugs, while further research on this natural agent is needed.

The circadian rhythm key gene ARNTL2: a novel prognostic biomarker for immunosuppressive tumor microenvironment identification and immunotherapy outcome prediction in human cancers.

Background: Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) belongs to the b HLH- PAS domain transcription factor family and is one of the key clock genes that control the circadian rhythm. ARNTL2 plays an important role in human biological functions. However, its role in various tumors, especially in the tumor immune microenvironment (TIME) and immunotherapy, remains unclear. Methods: We integrated data from cancer patients from multiple databases, including the Cancer Genome Atlas, Cancer Cell Lineage Encyclopedia, Genotype Tissue Expression, Human Protein Atlas, cBioPortal, TIMER, and ImmuCellAI, with data from a large clinical study, three immunotherapy cohorts, and in vitro experiments to investigate the involvement of ARNTL2 expression in cancer prognosis and immune response. Results: ARNTL2 displayed abnormal expression within most malignant tumors, and is significantly associated with poorer survival and pathologic staging. Through gene-set enrichment analysis (GSEA) and gene-set variation analysis (GSVA), we found that ARNTL2 not only regulates cell cycle-related functions to promote cell proliferation but also regulates autoimmunity-related functions of the innate and adaptive immune systems, and other immune-related signaling pathways. In addition, ARNTL2 overexpression contributes to an immunosuppressive tumor microenvironment that plays a key role in immunosuppression-related features, such as the expression of immunosuppression-related genes and pathways and the number of immunosuppressive-infiltrating cells, including regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). The group of patients with low ARNTL2 expression who received immune checkpoint inhibitors (ICI) therapy had better response rates and longer survival when compared to those with high ARNTL2 expression. Conclusion: The findings of this study suggest that ARNTL2 is a potential human oncogene that plays an important role in tumorigenesis and cancer immunity. Elevated ARNTL2 expression indicates an immunosuppressive tumor microenvironment. Targeting ARNTL2 in combination with ICI therapy could bring more significant therapeutic benefits to patients with cancer. Our study sheds light on the remarkable potential of ARNTL2 in tumor immunity and provides a novel perspective for anti-tumor strategies.

Oncogenic roles and related mechanisms of the long non-coding RNA MINCR in human cancers.

Long non-coding RNAs (lncRNAs) play vital roles in regulating epigenetic mechanisms and gene expression levels, and their dysregulation is closely associated with a variety of diseases such as cancer. Several studies have demonstrated that lncRNAs are dysregulated during tumor progression. Recently, the MYC-induced long non-coding RNA MINCR, a newly identified lncRNA, has been demonstrated to act as an oncogene in different cancers, including gallbladder cancer, hepatocellular cancer, colorectal cancer, non-small cell lung cancer, oral squamous cell carcinoma, nasopharyngeal cancer, and glioma. Moreover, MINCR has been reported to act as a biomarker in the prognosis of patients with different cancers. In this review, we summarize and analyze the oncogenic roles of MINCR in a variety of human cancers in terms of its clinical significance, biological functions, cellular activities, and regulatory mechanism. Our analysis of the literature suggests that MINCR has potential as a novel biomarker and therapeutic target in human cancers.

Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead.

KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging. Among the different known mutants, KRasG12C has been proved to be successfully targeted recently. Several covalent inhibitors selectively targeting KRasG12C have shown promising efficacy against cancers harboring KRASG12C mutation in clinical trials and AMG510 (sotorasib) has been approved for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer. However, the overall responsive rate of KRasG12C inhibitors was around 50% in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable. It is of great importance to discover biomarkers to distinguish patients who are likely benefitted. Moreover, adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies. Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRasG12C inhibitors in preclinical settings. This review summarized the recent progress of covalent KRasG12C inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

Mammaglobin-A Expression Is Highly Specific for Tumors Derived from the Breast, the Female Genital Tract, and the Salivary Gland.

Human mammaglobin-A (SCGB2A2) is a secretory protein with an unknown function that is used as a diagnostic marker for breast cancer. However, other tumors can also express mammaglobin-A. To comprehensively study patterns of mammaglobin-A expression, a tissue microarray containing 16,328 samples from 128 different tumor types as well as 608 samples of 76 different normal tissue types was analyzed using immunohistochemistry. Mammaglobin-A positivity was found in only a few normal tissues, including luminal cells of the breast as well as endocervical and endometrial glands. In tumor tissues, 37 of 128 tumor categories showed mamma-globin-A staining, 32 of which were derived from one of four organs: breast (6 tumor categories), endometrium (5 tumor categories), ovary (5 tumor categories), and salivary glands (16 tumor categories). Only five additional tumor types showed occasional weak mammaglobin positivity, including medullary thyroid cancer, teratoma of the testis, squamous cell carcinoma of the skin and pharynx, and prostatic adenocarcinoma. Among 1139 evaluable invasive breast carcinomas of no special type, low mammaglobin-A immunostaining was linked to high BRE grade (p = 0.0011), loss of estrogen and progesterone receptor expression (p < 0.0001 each), and triple-negative status (p < 0.0001) but not to patient survival. In endometrial cancer, mammaglobin-A loss was linked to an advanced tumor stage (p = 0.0198). Our data characterize mammaglobin-A as a highly specific marker for tumors derived from either the breast, female genitals, or salivary gland.

PD-L1 expression and CD8 positive lymphocytes in human neoplasms: A tissue microarray study on 11,838 tumor samples.

BACKGROUND: Programmed death ligand 1 (PD-L1) is the target of immune checkpoint inhibitor therapies in a growing number of tumor types, but a unanimous picture on PD-L1 expression across cancer types is lacking. MATERIALS AND METHODS: We analyzed immunohistochemical PD-L1 expression in 11,838 samples from 118 human tumor types and its relationship with tumor infiltrating CD8 positive lymphocytes. RESULTS: At a cut-off level of 10% positive tumor cells, PD-L1 positivity was seen in 85 of 118 (72%) tumor types, including thymoma (100% positive), Hodgkin's lymphoma (93%), anaplastic thyroid carcinoma (76%), Kaposi sarcoma (71%), sarcomatoid urothelial carcinoma (71%), and squamous cell carcinoma of the penis (67%), cervix (65%), floor of the mouth (61%), the lung (53%), and pharynx (50%). In immune cells, PD-L1 positivity was detectable in 103 (87%) tumor types, including tumors of haematopoetic and lymphoid tissues (75% to 100%), Warthin tumors of the parotid glands (95%) and Merkel cell carcinoma (82%). PD-L1 positivity in tumor cells was significantly correlated with the number of intratumoral CD8 positive lymphocytes across all tumor types as well as in individual tumor types, including serous carcinoma of the ovary, invasive breast carcinoma of no special type, intestinal gastric adenocarcinoma, and liposarcoma (p< 0.0001 each). CONCLUSIONS: PD-L1 expression in tumor and inflammatory cells is found in a wide range of human tumor types. Higher rates of tumor infiltrating CD8 positive lymphocytes in PD-L1 positive than in PD-L1 negative cancers suggest that the antitumor immune response may trigger tumoral PD-L1 expression.

Signals transduced by Eph receptors and ephrin ligands converge on MAP kinase and AKT pathways in human cancers.

Eph receptors, the largest known family of receptor tyrosine kinases, and ephrin ligands have been implicated in a variety of human cancers. The novel bidirectional signaling events initiated by binding of Eph receptors to their cognate ephrin ligands modulate many cellular processes such as proliferation, metastasis, angiogenesis, invasion, and apoptosis. The relationships between the abundance of a unique subset of Eph receptors and ephrin ligands with associated cellular processes indicate a key role of these molecules in tumorigenesis. The combinatorial expression of these molecules converges on MAP kinase and/or AKT/mTOR signaling pathways. The intracellular target proteins of the initial signal may, however, vary in some cancers. Furthermore, we have also described the commonality of up- and down-regulation of individual receptors and ligands in various cancers. The current state of research in Eph receptors illustrates MAP kinase and mTOR pathways as plausible targets for therapeutic interventions in various cancers.