bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Targeted Imaging of Colonic Tumors in Smad3−/− Mice Discriminates Cancer and Inflammation
Authors: Deane Natasha G. , Manning H. Charles , Foutch A. Coe , Washington M. Kay , Aronow Bruce A. , Bornhop Darryl J. , Coffey Robert J.
Published: March 2024

Abstract
The peripheral benzodiazepine receptor (PBR) is a trans-mitochondrial membrane protein that modulates steroid biosynthesis. Recently, up-regulation and nuclear localization of PBR has been shown to be associated with colon, prostate, and breast cancer. PBR has been targeted by the exogenous synthetic ligand, PK11195, for various purposes including imaging. To capitalize on these observations, we developed a high-throughput, noninvasive, in vivo imaging approach to detect spontaneously arising colonic tumors in mice using a novel PBR-targeted molecular imaging agent (NIR-conPK11195). NIR-conPK11195 localized and was retained in colonic adenomas and carcinomas in Smad3−/− mice but not in non-neoplastic hamartomas or chronically inflamed colonic tissue. Using a fluorescence signal-to-noise ratio of ≥4-fold 13 h after injection of the agent, we detected colonic tumors with a sensitivity of 67% and a specificity of 86% in a cohort of 37 Smad3−/− mice and control littermates. Furthermore, using oral administration of dextran sulfate to induce colonic inflammation, we showed that the clearance profile of NIR-conPK11195 distinguished transient uptake in inflammatory tissue from longer term retention in tumors. Taken together, these results indicate that NIR-conPK11195 is a promising optical molecular imaging tool to rapidly screen for colonic tumors in mice and to discriminate inflammation from cancer. (Mol Cancer Res 2007;5(4):341–9)
Data from Transforming Growth Factor-β1 Induces Tissue Inhibitor of Metalloproteinase-1 Expression via Activation of Extracellular Signal-Regulated Kinase and Sp1 in Human Fibrosarcoma Cells
Authors: Kwak Hee-Jin , Park Myung-Jin , Cho Hyeyoung , Park Chang-Min , Moon Sang-Ik , Lee Hyung-Chan , Park In-Chul , Kim Mi-Suk , Rhee Chang Hun , Hong Seok-Il
Published: March 2024

Abstract
The net balance of matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) system has been known to be a key factor in tumor cell invasion. In the present study, we investigated the molecular mechanisms of anti-invasive and antimigrative activity of transforming growth factor (TGF)-β1 on HT1080 human fibrosarcoma cells. In in vitro Matrigel invasion and Transwell migration assays, TGF-β1 dose-dependently inhibited the invasion and migration of HT1080 cells, respectively. Gelatin zymography, Western blot, and real-time PCR analysis showed that TGF-β1 enhanced the expression and secretion of MMP-2, TIMP-1, and, to a lesser degree, MMP-9 but not membrane type 1-MMP and TIMP-2. The addition of recombinant TIMP-1 protein reduced the Matrigel invasion and Transwell migration of HT1080 cells, similar to TGF-β1. Because augmentation of TIMP-1 might be the major factor for the anti-invasive and antimigrative activity of TGF-β1, we investigated possible molecular mechanisms responsible for the expression of TIMP-1 induced by TGF-β1. Treatment of HT1080 cells with TGF-β1 rapidly phosphorylated three mitogen-activated protein kinases [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase] and Akt. Among these kinases, the inhibition of only ERK1/2 pathway by PD98059, a specific inhibitor of MAPK/ERK kinase(MEK)-1, and transfection of dominant-negative MEK 1 effectively blocked the TIMP-1 induction by TGF-β1. Mithramycin, a specific inhibitor of Sp1 transcription factor, but not curcumin, an inhibitor of activator protein-1, and transfection of Sp1 small interfering RNA significantly inhibited the TGF-β1-induced expression of TIMP-1. In addition, electrophoretic mobility shift assay showed that TGF-β1 up-regulated Sp1 DNA-binding activity, and PD98059 and mithramycin effectively inhibited these events. Finally, pretreatment of HT1080 cells with PD98059 and mithramycin, but not curcumin, restored the invasive activity of these cells. Taken together, these data suggest that TGF-β1 modulates the net balance of the MMPs/TIMPs the systems in HT1080 cells for anti-invasion and antimigration by augmenting TIMP-1 through ERK1/2 pathway and Sp1 transcription factor. (Mol Cancer Res 2006;4(3):209–20)
Data from A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1
Authors: Wirawan Aditya , Tajima Ken , Takahashi Fumiyuki , Mitsuishi Yoichiro , Winardi Wira , Hidayat Moulid , Hayakawa Daisuke , Matsumoto Naohisa , Izumi Kenta , Asao Tetsuhiko , Ko Ryo , Shimada Naoko , Takamochi Kazuya , Suzuki Kenji , Abe Masaaki , Hino Okio , Sekido Yoshitaka , Takahashi Kazuhisa
Published: March 2024

Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial–mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK–AKT–GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance.
Implications:
This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.
Data from Inflammation-Induced Metastatic Colonization of the Lung Is Facilitated by Hepatocyte Growth Factor-Secreting Monocyte-Derived Macrophages
Authors: Arif Arif A. , Huang Yu-Hsuan , Freeman Spencer A. , Atif Jawairia , Dean Pamela , Lai Jacqueline C.Y. , Blanchet Marie-Renee , Wiegand Kimberly C. , McNagny Kelly M. , Underhill T. Michael , Gold Michael R. , Johnson Pauline , Roskelley Calvin D.
Published: March 2024

Abstract
A rate-limiting step for circulating tumor cells to colonize distant organ sites is their ability to locate a microenvironmental niche that supports their survival and growth. This can be achieved by features intrinsic to the tumor cells and/or by the conditioning of a “premetastatic” niche. To determine if pulmonary inflammation promotes the latter, we initiated models for inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced sterile inflammation before introducing tumor cells with low metastatic potential into the circulation. All types of inflammation increased the end-stage metastatic burden of the lungs 14 days after tumor cell inoculation without overtly affecting tumor extravasation. Instead, the number and size of early micrometastatic lesions found within the interstitial tissues 96 hours after tumor cell inoculation were increased in the inflamed lungs, coincident with increased tumor cell survival and the presence of nearby inflammation-induced monocyte-derived macrophages (MoDM; CD11b+CD11c+). Remarkably, the adoptive transfer of these MoDM was sufficient to increase lung metastasis in the absence of inflammation. These inflammation-induced MoDM secrete a number of growth factors and cytokines, one of which is hepatocyte growth factor (HGF), that augmented tumor cell survival under conditions of stress in vitro. Importantly, blocking HGF signaling with the cMET inhibitor capmatinib abolished inflammation-induced early micrometastatic lesion formation in vivo. These findings indicate that inflammation-induced MoDM and HGF in particular increase the efficiency of early metastatic colonization in the lung by locally preconditioning the microenvironment.
Implications:
Inflammation preconditions the distant site microenvironment to increase the metastatic potential of tumor cells that arrive there.
Data from A Novel miR-146a-POU3F2/SMARCA5 Pathway Regulates Stemness and Therapeutic Response in Glioblastoma
Authors: Cui Tiantian , Bell Erica H. , McElroy Joseph , Liu Kevin , Sebastian Ebin , Johnson Benjamin , Gulati Pooja Manchanda , Becker Aline Paixao , Gray Ashley , Geurts Marjolein , Subedi Depika , Yang Linlin , Fleming Jessica L. , Meng Wei , Barnholtz-Sloan Jill S. , Venere Monica , Wang Qi-En , Robe Pierre A. , Haque S. Jaharul , Chakravarti Arnab
Published: March 2024

Abstract
Rapid tumor growth, widespread brain-invasion, and therapeutic resistance critically contribute to glioblastoma (GBM) recurrence and dismal patient outcomes. Although GBM stem cells (GSC) are shown to play key roles in these processes, the molecular pathways governing the GSC phenotype (GBM-stemness) remain poorly defined. Here, we show that epigenetic silencing of miR-146a significantly correlated with worse patient outcome and importantly, miR-146a level was significantly lower in recurrent tumors compared with primary ones. Further, miR-146a overexpression significantly inhibited the proliferation and invasion of GBM patient-derived primary cells and increased their response to temozolomide (TMZ), both in vitro and in vivo. Mechanistically, miR-146a directly silenced POU3F2 and SMARCA5, two transcription factors that mutually regulated each other, significantly compromising GBM-stemness and increasing TMZ response. Collectively, our data show that miR-146a–POU3F2/SMARCA5 pathway plays a critical role in suppressing GBM-stemness and increasing TMZ-response, suggesting that POU3F2 and SMARCA5 may serve as novel therapeutic targets in GBM.
Implications:
miR-146a predicts favorable prognosis and the miR-146a–POU3F2/SMARCA5 pathway is important for the suppression of stemness in GBM.
Data from Stromal CAVIN1 Controls Prostate Cancer Microenvironment and Metastasis by Modulating Lipid Distribution and Inflammatory Signaling
Authors: Low Jin-Yih , Brennen W. Nathaniel , Meeker Alan K. , Ikonen Elina , Simons Brian W. , Laiho Marikki
Published: March 2024

Abstract
Lipid uptake occurs through caveolae, plasma membrane invaginations formed by caveolins (CAV) and caveolae-associated protein 1 (CAVIN1). Genetic alterations of CAV1N1 and CAV1 modify lipid metabolism and underpin lipodystrophy syndromes. Lipids contribute to tumorigenesis by providing fuel to cancer metabolism and supporting growth and signaling. Tumor stroma promotes tumor proliferation, invasion, and metastasis, but how stromal lipids influence these processes remain to be defined. Here, we show that stromal CAVIN1 regulates lipid abundance in the prostate cancer microenvironment and suppresses metastasis. We show that depletion of CAVIN1 in prostate stromal cells markedly reduces their lipid droplet accumulation and increases inflammation. Stromal cells lacking CAVIN1 enhance prostate cancer cell migration and invasion. Remarkably, they increase lipid uptake and M2 inflammatory macrophage infiltration in the primary tumors and metastasis to distant sites. Our data support the concept that stromal cells contribute to prostate cancer aggressiveness by modulating lipid content and inflammation in the tumor microenvironment.
Implications:
This study showed that stromal CAVIN1 suppresses prostate cancer metastasis by modulating tumor microenvironment, lipid content, and inflammatory response.
Data from Platelet-Coated Circulating Tumor Cells Are a Predictive Biomarker in Patients with Metastatic Castrate-Resistant Prostate Cancer
Authors: Chai Shoujie , Matsumoto Nicholas , Storgard Ryan , Peng Chen-Ching , Aparicio Ana , Ormseth Benjamin , Rappard Kate , Cunningham Katherine , Kolatkar Anand , Nevarez Rafael , Tu Kai-Han , Hsu Ching-Ju , Malihi Paymaneh , Corn Paul , Zurita Amado , Hicks James , Kuhn Peter , Ruiz-Velasco Carmen
Published: March 2024

Abstract
Metastatic castration-resistant prostate cancer (mCRPC) includes a subset of patients with particularly unfavorable prognosis characterized by combined defects in at least two of three tumor suppressor genes: PTEN, RB1, and TP53 as aggressive variant prostate cancer molecular signature (AVPC-MS). We aimed to identify circulating tumor cells (CTC) signatures that could inform treatment decisions of patients with mCRPC with cabazitaxel–carboplatin combination therapy versus cabazitaxel alone. Liquid biopsy samples were collected prospectively from 79 patients for retrospective analysis. CTCs were detected, classified, enumerated through a computational pipeline followed by manual curation, and subjected to single-cell genome-wide copy-number profiling for AVPC-MS detection. On the basis of immunofluorescence intensities, detected rare cells were classified into 8 rare-cell groups. Further morphologic characterization categorized CTC subtypes from 4 cytokeratin-positive rare-cell groups, utilizing presence of mesenchymal features and platelet attachment. Of 79 cases, 77 (97.5%) had CTCs, 24 (30.4%) were positive for platelet-coated CTCs (pc.CTCs) and 25 (38.5%) of 65 sequenced patients exhibited AVPC-MS in CTCs. Survival analysis indicated that the presence of pc.CTCs identified the subset of patients who were AVPC-MS–positive with the worst prognosis and minimal benefit from combination therapy. In AVPC-MS–negative patients, its presence showed significant survival improvement from combination therapy. Our findings suggest the presence of pc.CTCs as a predictive biomarker to further stratify AVPC subsets with the worst prognosis and the most significant benefit of additional platinum therapy.
Implications:
HDSCA3.0 can be performed with rare cell detection, categorization, and genomic characterization for pc.CTC identification and AVPC-MS detection as a potential predictive biomarker of mCRPC.
Data from mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment
Authors: Haas Michael S. , Kagey Michael H. , Heath Heidi , Schuerpf Franziska , Rottman James B. , Newman Walter
Published: March 2024

Abstract
Dickkopf-1 (DKK1), a secreted modulator of Wnt signaling, is overexpressed in many cancers, is often associated with worse clinical outcomes, and has been shown to have immunosuppressive effects. DKN-01 is an IgG4 clinical stage antibody that potently and specifically neutralizes human and murine DKK1 and has recently completed a promising study in combination with pembrolizumab in patients with gastric/gastroesophageal junction cancer. The purpose of this study is to characterize a murine version of DKN-01 (mDKN-01) and to better understand its mechanism of action. We examined the efficacy of mDKN-01 in both melanoma and metastatic breast cancer models. Immune depletion experiments revealed a requirement for natural killer (NK) but not B and T cells for tumor growth inhibition. mDKN-01 treatment promotes the induction of the NK-activating cytokines IL15 and IL33 as well as an enhanced recruitment of CD45+ cells. Other treatment-related changes include a reduction of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) in the tumor and spleen and the upregulation of PD-L1 on MDSCs. In addition, mDKN-01 has a marked effect at reducing pulmonary metastases in the mouse 4T1 breast cancer model. Finally, the mDKN-01/anti-PD-1 combination was more effective at inhibiting melanoma growth than mDKN-01 alone. Taken together, our data demonstrate that mDKN-01 has efficacy by blocking the immunosuppressive effects of DKK1 in the tumor microenvironment (TME) and provides insight into the clinical activity observed with DKN-01–based treatment.
Implications:
mDKN-01 reverses a DKK1-mediated innate immune suppression in the TME and has additive efficacy with a PD-1 inhibitor.
Data from Suppression of SIN3A by miR-183 Promotes Breast Cancer Metastasis
Authors: Davenport Mackenzie L. , Davis Mara R. , Davenport Baylea N. , Crossman David K. , Hall Aaron , Pike Jason , Harada Shuko , Hurst Douglas R. , Edmonds Mick D.
Published: March 2024

Abstract
Recent work has established that SWI-independent-3 (SIN3) chromatin modification complexes play key roles in cancer progression. We previously demonstrated that knockdown of SIN3A expression promotes human breast cancer cell invasion and metastasis; however, the levels of SIN3A in patient breast carcinoma are not known. We therefore examined SIN3A mRNA and protein in patient tissues and determined that SIN3A expression is lower in breast carcinoma relative to normal breast. Given the 3′—untranslated region (UTR) of SIN3A has several conserved binding sites for oncogenic miRNA, we hypothesized that SIN3A is targeted by miRNA and found that ectopic miR-183 results in decreased SIN3A in breast carcinoma cell lines. Functionally, we demonstrate that miR-183 promotes breast cancer cell migration and invasion in a SIN3A-dependent manner and ectopic miR-183 promotes metastasis in vivo. Patients with breast cancer with high levels of miR-183 and low levels of SIN3A have the shortest overall survival. Given the critical link between metastasis and survival in patients with breast cancer, it is of utmost importance to identify clinically relevant genes involved in metastasis. Here, we report for the first time the aberrant expression of the putative metastasis suppressing gene SIN3A in human breast cancers and propose a mechanism of SIN3A suppression by miR-183.
Implications:
SIN3A expression is decreased in metastatic breast cancer in part due to miR-183.
Data from In Vitro Insertional Mutagenesis Screen Identifies Novel Genes Driving Breast Cancer Metastasis
Authors: Miskey Csaba , Botezatu Lacramioara , Temiz Nuri A. , Gogol-Döring Andreas , Bartha Áron , Győrffy Balázs , Largaespada David A. , Ivics Zoltán , Sebe Attila
Published: March 2024

Abstract
Metastasis, a complex, multistep process, is responsible for the overwhelming majority of cancer-related deaths. Despite its devastating consequences, it is not possible to effectively treat cancer that has spread to vital organs, the mechanisms leading to metastasis are still poorly understood, and the catalog of metastasis promoting genes is still incomprehensive. To identify new driver genes of metastasis development, we performed an in vitro Sleeping Beauty transposon-based forward genetic screen in nonmetastatic SKBR3 human breast cancer cells. Boyden chamber-based matrix invasion assays were used to harvest cells that acquired a de novo invasive phenotype. Using targeted RNA sequencing data from 18 pools of invasive cells, we carried out a gene-centric candidate gene prediction and identified established and novel metastasis driver genes. Analysis of these genes revealed their association with metastasis related processes and we further established their clinical relevance in metastatic breast cancer. Two novel candidate genes, G protein–coupled receptor kinase interacting ArfGAP 2 (GIT2) and muscle-associated receptor tyrosine kinase (MUSK), were functionally validated as metastasis driver genes in a series of in vitro and in vivo experimental metastasis models. We propose that our robust and scalable approach will be a useful addition to the toolkit of methodologic resources used to identify genes driving cancer metastasis.
Implications:
Novel metastasis drivers were identified in a human breast cancer cell line by performing an in vitro, Sleeping Beauty transposon-based forward genetic screen and an RNA fusion-based candidate gene prediction.
Data from Transcriptomes of Prostate Cancer with TMPRSS2:ERG and Other ETS Fusions
Authors: Stopsack Konrad H. , Su Xiaofeng A. , Vaselkiv J. Bailey , Graff Rebecca E. , Ebot Ericka M. , Pettersson Andreas , Lis Rosina T. , Fiorentino Michelangelo , Loda Massimo , Penney Kathryn L. , Lotan Tamara L. , Mucci Lorelei A.
Published: March 2024

Abstract
The most common somatic event in primary prostate cancer is a fusion between the androgen-related TMPRSS2 gene and the ERG oncogene. Tumors with these fusions, which occur early in carcinogenesis, have a distinctive etiology. A smaller subset of other tumors harbor fusions between TMPRSS2 and members of the ETS transcription factor family other than ERG. To assess the genomic similarity of tumors with non-ERG ETS fusions and those with fusions involving ERG, this study derived a transcriptomic signature of non-ERG ETS fusions and assessed this signature and ERG-related gene expression in 1,050 men with primary prostate cancer from three independent population-based and hospital-based studies. Although non-ERG ETS fusions involving ETV1, ETV4, ETV5, or FLI1 were individually rare, they jointly accounted for one in seven prostate tumors. Genes differentially regulated between non-ERG ETS tumors and tumors without ETS fusions showed similar differential expression when ERG tumors and tumors without ETS fusions were compared (differences explained: R2 = 69–77%), including ETS-related androgen receptor (AR) target genes. Differences appeared to result from similarities among ETS tumors rather than similarities among non-ETS tumors. Gene sets associated with ERG fusions were consistent with gene sets associated with non-ERG ETS fusions, including fatty acid and amino acid metabolism, an observation that was robust across cohorts.
Implications:
Considering ETS fusions jointly may be useful for etiologic studies on prostate cancer, given that the transcriptome is profoundly impacted by ERG and non-ERG ETS fusions in a largely similar fashion, most notably genes regulating metabolic pathways.
Data from Sox2 Is an Oncogenic Driver of Small-Cell Lung Cancer and Promotes the Classic Neuroendocrine Subtype
Authors: Voigt Ellen , Wallenburg Madeline , Wollenzien Hannah , Thompson Ethan , Kumar Kirtana , Feiner Joshua , McNally Moira , Friesen Hunter , Mukherjee Malini , Afeworki Yohannes , Kareta Michael S.
Published: March 2024

Abstract
Although many cancer prognoses have improved in the past 50 years due to advancements in treatments, there has been little improvement in therapies for small-cell lung cancer (SCLC). One promising avenue to improve treatment for SCLC is to understand its underlying genetic alterations that drive its formation, growth, and cellular heterogeneity. RB1 loss is one key driver of SCLC, and RB1 loss has been associated with an increase in pluripotency factors such as SOX2. SOX2 is highly expressed and amplified in SCLC and has been associated with SCLC growth. Using a genetically engineered mouse model, we have shown that Sox2 is required for efficient SCLC formation. Furthermore, genome-scale binding assays have indicated that SOX2 can regulate key SCLC pathways such as NEUROD1 and MYC. These data suggest that SOX2 can be associated with the switch of SCLC from an ASCL1 subtype to a NEUROD1 subtype. Understanding this genetic switch is key to understanding such processes as SCLC progression, cellular heterogeneity, and treatment resistance.
Implications:
Understanding the molecular mechanisms of SCLC initiation and development are key to opening new potential therapeutic options for this devastating disease.
Data from KDM6A Depletion in Breast Epithelial Cells Leads to Reduced Sensitivity to Anticancer Agents and Increased TGFβ Activity
Authors: Xiao Jin-Fen , Kua Ley-Fang , Ding Ling-Wen , Sun Qiao-Yang , Myint Khine Nyein , Chia Xiu-Rong , Venkatachalam Nachiyappan , Loh Xinyi , Duex Jason E. , Neang Vanessa , Zhou Siqin , Li Ying , Yang Henry , Koeffler H. Phillip , Theodorescu Dan
Published: March 2024

Abstract
KDM6A, an X chromosome-linked histone lysine demethylase, was reported to be frequently mutated in many tumor types including breast and bladder cancer. However, the functional role of KDM6A is not fully understood. Using MCF10A as a model of non-tumorigenic epithelial breast cells, we found that silencing KDM6A promoted cell migration and transformation demonstrated by the formation of tumor-like acini in three-dimensional culture. KDM6A loss reduced the sensitivity of MCF10A cells to therapeutic agents commonly used to treat patients with triple-negative breast cancer and also induced TGFβ extracellular secretion leading to suppressed expression of cytotoxic genes in normal human CD8+ T cells in vitro. Interestingly, when cells were treated with TGFβ, de novo synthesis of KDM6A protein was suppressed while TGFB1 transcription was enhanced, indicating a TGFβ/KDM6A-negative regulatory axis. Furthermore, both KDM6A deficiency and TGFβ treatment promoted disorganized acinar structures in three-dimensional culture, as well as transcriptional profiles associated with epithelial-to-mesenchymal transition and metastasis, suggesting KDM6A depletion and TGFβ drive tumor progression.
Implications:
Our study provides the preclinical rationale for evaluating KDM6A and TGFβ in breast tumor samples as predictors for response to chemo and immunotherapy, informing personalized therapy based on these findings.
Data from Hypertension Promotes the Proliferation and Migration of ccRCC Cells by Downregulation of TIMP3 in Tumor Endothelial Cells through the miR-21–5p/TGFBR2/P38/EGR1 Axis
Authors: Wang Chenguang , Xu Haibo , Liao Xinhui , Wang Weiming , Wu Wanjun , Li Wujiao , Niu Liman , Li Zhichao , Li Aolin , Sun Yangyang , Huang Weiren , Song Fei
Published: March 2024

Abstract
Recent studies have demonstrated that hypertension correlates with tumorigenesis and prognosis of clear-cell renal cell carcinoma (ccRCC); however, the underlying molecular mechanisms remain unclear. By analyzing bulk and single-cell RNA sequencing data and experimental examining of surgical excised ccRCC samples, we found that tissue inhibitors of metalloproteinases 3 (TIMP3), a pivotal paracrine factor in suppressing tumor progression, was significantly reduced in the tumor endothelial cells of patients with hypertensive ccRCC. Besides, in tumor xenograft of NCG mouse model, compared with saline normotensive group the expression of TIMP3 was significantly decreased in the angiotensin II–induced hypertension group. Treating human umbilical vein endothelial cells (HUVEC) with the plasma of patients with hypertensive ccRCC and miR-21–5p, elevated in the plasma of patients with hypertensive ccRCC, reduced the expression of TIMP3 compared with normotensive and control littermates. We also found that the inhibition of TIMP3 expression by miR-21–5p was not through directly targeting at 3′UTR of TIMP3 but through suppressing the expression of TGFβ receptor 2 (TGFBR2). In addition, the knockout of TGFBR2 reduced TIMP3 expression in HUVECs through P38/EGR1 (early growth response protein 1) signaling axis. Moreover, via coculture of ccRCC cell lines with HUVECs and mouse tumor xenograft model, we discovered that the TIMP3 could suppress the proliferation and migration of ccRCC.
Implications:
Overall, our findings shed new light on the role of hypertension in promoting the progression of ccRCC and provide a potential therapeutic target for patients with ccRCC with hypertension.
Data from The Spatial Context of Tumor-Infiltrating Immune Cells Associates with Improved Ovarian Cancer Survival
Authors: Steinhart Benjamin , Jordan Kimberly R. , Bapat Jaidev , Post Miriam D. , Brubaker Lindsay W. , Bitler Benjamin G. , Wrobel Julia
Published: March 2024

Abstract
Ovarian cancer is the deadliest gynecologic malignancy. Multi-omics techniques have provided a platform for improved predictive modeling of therapy response and patient outcomes. While high-grade serous carcinoma (HGSOC) tumors are immunogenic and numerous studies have defined positive correlation to immune cell infiltration, immunotherapies in clinical trials have exhibited low efficacy rates. There is a significant need to better comprehend the role and composition of immune cells in mediating ovarian cancer therapeutic response and progression. We performed multiplex IHC with an HGSOC tissue microarray (n = 127) to characterize the immune cell composition within tumors. After analyzing the composition and spatial context of T cells (CD4/CD8), macrophages (CD68), and B cells (CD19) within the tumor, we found that increased B-cell and CD4 T-cell presence correlated with overall survival. More importantly, we observed that the proximity between tumor-associated macrophages and B cells or CD4 T cells significantly correlated with overall survival.
Implications:
The results highlight the antitumor role of B cells and CD4 T cells, and that the spatial interactions between immune cell types are a novel predictor of therapeutic response and patient outcomes.
Data from Bowman Birk Inhibitor Concentrate and Oral Leukoplakia: A Randomized Phase IIb Trial
Authors: Armstrong William B. , Taylor Thomas H. , Kennedy Ann R. , Melrose Raymond J. , Messadi Diana V. , Gu Mai , Le Anh D. , Perloff Marjorie , Civantos Francisco , Goodwin William Jarrard , Wirth Lori J. , Kerr Alexander Ross , Meyskens Frank L.
Published: March 2024

Abstract
Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering “Green” chemoprevention. Cancer Prev Res; 6(5); 410–8. ©2013 AACR.
Data from Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer
Authors: Vogel Victor G. , Costantino Joseph P. , Wickerham D. Lawrence , Cronin Walter M. , Cecchini Reena S. , Atkins James N. , Bevers Therese B. , Fehrenbacher Louis , Pajon Eduardo R. , Wade James L. , Robidoux André , Margolese Richard G. , James Joan , Runowicz Carolyn D. , Ganz Patricia A. , Reis Steven E. , McCaskill-Stevens Worta , Ford Leslie G. , Jordan V. Craig , Wolmark Norman
Published: March 2024

Abstract
The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)–approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05–1.47) and for noninvasive disease, 1.22 (95% CI, 0.95–1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36–0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12–0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60–0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer. Cancer Prev Res; 3(6); 696–706. ©2010 AACR.
Data from Dietary Tricin Suppresses Inflammation-Related Colon Carcinogenesis in Male Crj: CD-1 Mice
Authors: Oyama Takeru , Yasui Yumiko , Sugie Shigeyuki , Koketsu Mamoru , Watanabe Kunitomo , Tanaka Takuji
Published: March 2024

Abstract
The flavone 4′,5,7-trihydroxy-3′,5′-dimethoxyflavone (tricin) present in rice, oats, barley, and wheat exhibits antigrowth activity in several human cancer cell lines and anti-inflammatory potential. However, the chemopreventive activity has not yet been elucidated in preclinical animal models of colorectal cancer. This study was designed to determine whether dietary tricin exerts inflammation-associated colon carcinogenesis induced by azoxymethane and dextran sulfate sodium in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (10 mg/kg body weight) and followed by a 1-week exposure to dextran sulfate sodium (1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the experimental diet containing 50 or 250 ppm tricin. The experiment was terminated at week 18 to determine the chemopreventive efficacy of tricin. In addition, the effects of dietary tricin on the expression of several inflammatory cytokines, including tumor necrosis factor (TNF)-α, were assayed. The development of colonic adenomas and adenocarcinomas was significantly reduced by feeding with 50 and 250 ppm tricin, respectively. Dietary tricin also significantly reduced the proliferation of adenocarcinoma cells as well as the numbers of mitoses/anaphase bridging in adenocarcinoma cells. The dietary administration with tricin significantly inhibited the expression of TNF-α in the nonlesional cypts. Our findings that dietary tricin inhibits inflammation-related mouse colon carcinogenesis by suppressing the expression of TNF-α in the nonlesional cyrpts and the proliferation of adenocarcinomas suggest a potential use of tricin for clinical trials of colorectal cancer chemoprevention.
Data from A Model of Gene-Environment Interaction Reveals Altered Mammary Gland Gene Expression and Increased Tumor Growth following Social Isolation
Authors: Williams J. Bradley , Pang Diana , Delgado Bertha , Kocherginsky Masha , Tretiakova Maria , Krausz Thomas , Pan Deng , He Jane , McClintock Martha K. , Conzen Suzanne D.
Published: March 2024

Abstract
Clinical studies have revealed that social support improves the outcome of cancer patients, whereas epidemiologic studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise molecular consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible preclinical models are needed to study the mechanisms whereby an adverse environment affects gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a preclinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the premalignant mammary gland. Chronic social isolation was associated with up-regulated lipid synthesis and glycolytic pathway gene expression—both pathways are known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes in premalignant mammary tissue, isolated mice subsequently developed a significantly larger mammary gland tumors burden compared with group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared with group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways gene expression favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g., fatty acid synthesis) for preventive intervention in breast cancer.
Data from Two Good Choices to Prevent Breast Cancer: Great Taste, Less Filling
Authors: Hortobagyi Gabriel N. , Brown Powel H.
Published: March 2024

Abstract
An important report in this issue of the journal by Vogel et al. (beginning on p. 696) discloses long-term follow-up data of the Study of Tamoxifen and Raloxifene (STAR) showing persisting strong effects of both drugs in preventing invasive and noninvasive breast cancer after drugs were stopped in 2006. In addition, safety improved with longer follow-up (median of 81 months versus 47 months for the initial report). For 12 years, the public has avoided Food and Drug Administration–approved tamoxifen or raloxifene for breast cancer risk reduction; it is time to reemphasize the great preventive benefit of these agents to the public. Cancer Prev Res; 3(6); 681–5. ©2010 AACR.
Data from Favoritism in DNA Methylation
Authors: Hitchins Megan P. , Ward Robyn L.
Published: March 2024

Abstract
This perspective on Candiloro and Dobrovic (beginning on p. 862 in this issue of the journal) highlights the interplay between epigenetic aberrations and underlying DNA sequence changes and illustrates how these alterations may predispose individuals to cancer. Candiloro and Dobrovic clearly show that particular genotypes of the MGMT gene are associated with its methylation in healthy individuals. Aberrant MGMT methylation may identify individuals who could be targeted for cancer screening and chemoprevention strategies.
Data from Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial
Authors: Meyskens Frank L. , McLaren Christine E. , Pelot Daniel , Fujikawa-Brooks Sharon , Carpenter Philip M. , Hawk Ernest , Kelloff Gary , Lawson Michael J. , Kidao Jayashri , McCracken John , Albers C. Gregory , Ahnen Dennis J. , Turgeon D. Kim , Goldschmid Steven , Lance Peter , Hagedorn Curt H. , Gillen Daniel L. , Gerner Eugene W.
Published: March 2024

Abstract
Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (≥3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade ≥3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.
Data from Caffeic Acid Phenethyl Ester Suppresses the Proliferation of Human Prostate Cancer Cells through Inhibition of p70S6K and Akt Signaling Networks
Authors: Chuu Chih-Pin , Lin Hui-Ping , Ciaccio Mark F. , Kokontis John M. , Hause Ronald J. , Hiipakka Richard A. , Liao Shutsung , Jones Richard Baker
Published: March 2024

Abstract
Caffeic acid phenethyl ester (CAPE) is a bioactive component derived from honeybee hive propolis. CAPE has been shown to have antimitogenic, anticarcinogenic, and other beneficial medicinal properties. Many of its effects have been shown to be mediated through its inhibition of NF-κB signaling pathways. We took a systematic approach to uncover the effects of CAPE from hours to days on the signaling networks in human prostate cancer cells. We observed that CAPE dosage dependently suppressed the proliferation of LNCaP, DU-145, and PC-3 human prostate cancer cells. Administration of CAPE by gavage significantly inhibited the tumor growth of LNCaP xenografts in nude mice. Using LNCaP cells as a model system, we examined the effect of CAPE on gene expression, protein signaling, and transcriptional regulatory networks using micro-Western arrays and PCR arrays. We built a model of the impact of CAPE on cell signaling which suggested that it acted through inhibition of Akt-related protein signaling networks. Overexpression of Akt1 or c-Myc, a downstream target of Akt signaling, significantly blocked the antiproliferative effects of CAPE. In summary, our results suggest that CAPE administration may be useful as an adjuvant therapy for prostate and potentially other types of cancers that are driven by the p70S6K and Akt signaling networks. Cancer Prev Res; 5(5); 788–97. ©2012 AACR.
Data from Detection of MGMT Promoter Methylation in Normal Individuals Is Strongly Associated with the T Allele of the rs16906252 MGMT Promoter Single Nucleotide Polymorphism
Authors: Candiloro Ida L.M. , Dobrovic Alexander
Published: March 2024

Abstract
Methylation of the CpG island in the MGMT promoter region is a frequent event in several cancer types including colorectal cancer, lung cancer, lymphoma, and glioblastoma. A correlation between methylation and the T allele of the rs16906252 single nucleotide polymorphism (SNP) in colorectal carcinomas has previously been reported. As aberrant MGMT methylation can be an early event in tumor development, we tested the hypothesis that normal individuals possessing the T allele may be predisposed to somatic methylation at the MGMT promoter. Peripheral blood monononuclear cell DNA from 89 normal, healthy individuals was genotyped at rs1690625 and assessed for the methylation status of the MGMT promoter region using independent quantitative methodologies capable of detecting low-level methylation: MethyLight and Sensitive Melting Analysis after Real-time Methylation-Specific PCR (SMART-MSP). There was a strong association between presence of the T allele and detectable methylation (P = 0.00005) in the peripheral blood DNA. Furthermore, when a MSP assay flanking the SNP was used to amplify methylated sequences in heterozygotes, only the T allele was methylated. Thus, detectable somatic methylation of the MGMT promoter in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter SNP.
Data from Multiple Aberrations of Chromosome 3p Detected in Oral Premalignant Lesions
Authors: Tsui Ivy F.L. , Rosin Miriam P. , Zhang Lewei , Ng Raymond T. , Lam Wan L.
Published: March 2024

Abstract
The study of oral premalignant lesions (OPL) is crucial to the identification of initiating genetic events in oral cancer. However, these lesions are minute in size, making it a challenge to recover sufficient DNA from microdissected cells for comprehensive genomic analysis. As a step toward identifying genetic aberrations associated with oral cancer progression, we used tiling-path array comparative genomic hybridization to compare alterations on chromosome 3p for 71 OPLs against 23 oral squamous cell carcinomas. 3p was chosen because although it is frequently altered in oral cancers and has been associated with progression risk, its alteration status has only been evaluated at a small number of loci in OPLs. We identified six recurrent losses in this region that were shared between high-grade dysplasias and oral squamous cell carcinomas, including a 2.89-Mbp deletion spanning the FHIT gene (previously implicated in oral cancer progression). When the alteration status for these six regions was examined in 24 low-grade dysplasias with known progression outcome, we observed that they occurred at a significantly higher frequency in low-grade dysplasias that later progressed to later-stage disease (P < 0.003). Moreover, parallel analysis of all profiled tissues showed that the extent of overall genomic alteration at 3p increased with histologic stage. This first high-resolution analysis of chromosome arm 3p in OPLs represents a significant step toward predicting progression risk in early preinvasive disease and provides a keen example of how genomic instability escalates with progression to invasive cancer.