Carcinogenesis [JOURNAL]
Sun
200 papers
Exogenous or in situ vaccination to trigger clinical responses in pancreatic cancer.
Beatty GL, Jaffee EM
Carcinogenesis · 2024 Nov · PMID 39514560 · Full text
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease for which remarkable therapeutic resistance is the norm. Conventional immunotherapies, like immune checkpoint inhibitors, show limited efficacy in PDA due to a r...
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease for which remarkable therapeutic resistance is the norm. Conventional immunotherapies, like immune checkpoint inhibitors, show limited efficacy in PDA due to a remarkably immunosuppressive tumor microenvironment (TME) and systemic inflammation. This review discusses the potential of both exogenous and in situ vaccination strategies to overcome these barriers and enhance anti-tumor immunity in PDA. Exogenous vaccines, including whole-cell, dendritic cell, peptide, and nucleic acid-based vaccines, have shown varying degrees of promise but face challenges related to antigen selection, production complexities, and patient-specific factors. In contrast, in situ vaccination strategies leverage conventional cytotoxic therapies, such as chemotherapy and radiation therapy, to induce immunogenic cell death and modulate the TME with the aim to stimulate anti-tumor immunity. While preclinical studies support the use of in situ vaccination, balancing the stimulatory and inhibitory effects is likely fundamental to eliciting productive anti-tumor responses in patients. Ongoing research seeks to identify new innovative strategies that can harness the endogenous immune response and trigger in situ vaccination. Overall, while both vaccination approaches offer significant potential, further research and clinical trials will be needed to optimize these strategies for improving patient outcomes in PDA.
CAFomics: convergence to translation for precision stroma approaches.
McCabe IC, Peng XL, Kearney JF … +1 more , Yeh JJ
Carcinogenesis · 2024 Nov · PMID 39514556 · Full text
A noticeable characteristic of pancreatic ductal adenocarcinoma (PDAC) tumors is a dense tumor microenvironment with abundant and dense, desmoplastic stroma woven tightly with both cellular and matrix components. The hig...
A noticeable characteristic of pancreatic ductal adenocarcinoma (PDAC) tumors is a dense tumor microenvironment with abundant and dense, desmoplastic stroma woven tightly with both cellular and matrix components. The high stromal density is associated with higher intratumor pressures which, until the last decade, was largely assumed to be tumor protective, confirmed by early studies demonstrating that altering the stroma was effective in genetically engineered models of PDAC. However, clinical trials using these approaches have been disappointing. There is increasing recognition that stroma heterogeneity is much greater than initially thought with an explosion of investigation into cancer-associated fibroblast (CAF) subpopulations led by experimental and single-cell transcriptomic studies. This review summarizes and attempts to harmonize the current transcriptomic data of CAF subpopulations. Understanding the heterogeneity of CAFs, the matrix, and other tumor microenvironment features will be critical to developing effective therapeutic approaches. Identifying model systems that best recapitulate the clinical behavior and treatment response of human PDAC will be important. Examining subpopulations as defined by clinical outcome will remain a critical step in defining clinically impactful CAF subtypes in larger clinical cohorts. The future of precision oncology in PDAC will depend on the integration of precision tumor epithelial and precision stroma approaches.
From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression.
Graham S, Dmitrieva M, Vendramini-Costa DB … +4 more , Francescone R, Trujillo MA, Cukierman E, Wood LD
Carcinogenesis · 2024 Nov · PMID 39514554 · Full text
This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences....
This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.
Redefining pancreatic cancer management with tumor-agnostic precision medicine.
Reddy NK, Subbiah V
Carcinogenesis · 2024 Nov · PMID 39514550 · Publisher ↗
Precision oncology and tumor-agnostic drug development provide hope for enhancing outcomes among patients with pancreatic cancer. Tumor-agnostic therapies have emerged across various tumor types, driven by insights into...
Precision oncology and tumor-agnostic drug development provide hope for enhancing outcomes among patients with pancreatic cancer. Tumor-agnostic therapies have emerged across various tumor types, driven by insights into shared biomarkers. In the case of pancreatic cancer, the prevalence of the KRAS gene mutation is noteworthy. However, there exist other actionable alterations, such as BRCA1/2 mutations and fusion genes (BRAF, FGFR2, RET, NTRK, NRG1, and ALK), which present potential targets for therapy. Notably, tumor-agnostic drugs have demonstrated efficacy in specific subsets of pancreatic cancer patients who harbor these genetic alterations. Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers. Moreover, targeted therapies for BRAF V600, RET fusions, and HER2/neu overexpression have displayed promising results in specific subsets of pancreatic cancer patients. Emerging targets like NRG fusions, FGFR2 fusions, TP53 mutations, and KRAS G12C mutations present potential avenues for targeted therapy. Tumor-agnostic therapies have the potential to revolutionize pancreatic cancer treatment by focusing on specific genetic alterations. It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.
Inhibition of phospholipase D1 reduces pancreatic carcinogenesis in mice partly through a FAK-dependent mechanism.
Addassi HA, Krga I, Villarreal F … +4 more , LaComb JF, Frohman MA, Matsukuma K, Mackenzie GG
Carcinogenesis · 2025 Jan · PMID 39487573 · Full text
Phospholipase D (PLD) plays a critical role in cancer progression. However, its role in pancreatic cancer remains unclear. Thus, we evaluated the role of PLD1, one of two classical isoforms of PLD, in pancreatic carcinog...
Phospholipase D (PLD) plays a critical role in cancer progression. However, its role in pancreatic cancer remains unclear. Thus, we evaluated the role of PLD1, one of two classical isoforms of PLD, in pancreatic carcinogenesis in vivo. The role of PLD1 in tumor growth was evaluated by subcutaneously transplanting human MIA PaCa-2 cells expressing endogenous PLD1 levels (Ctr KD cells) or cells in which PLD1 was knocked down (Pld1 KD cells) into immunodeficient mice. Twenty days post-implantation, tumors that arose from Pld1-KD cells were significantly smaller, compared to controls (Ctr KD). Then, we assessed the role of PLD1 in the tumor microenvironment, by subcutaneously implanting mouse LSL-KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) cells into wild-type or PLD1 knockout (Pld1-/-) mice. Compared to wild type, tumor growth was attenuated in Pld1-/- mice by 39%, whereas treatment of Pld1-/- mice with gemcitabine reduced tumor growth by 79%. When PLD1 was ablated in LSL-KrasG12D;Ptf1Cre/+ (KC) mice, no reduction in acinar cell loss was observed, compared to KC mice. Finally, treatment of KC mice with a small molecule inhibitor of PLD1 and PLD2 (FIPI) significantly reduced acinar cell loss and cell proliferation, compared to vehicle-treated mice. Mechanistically, the effect of PLD on tumor growth is mediated, partly, by the focal adhesion kinase pathway. In conclusion, while PLD1 is a critical regulator of pancreatic xenograft and allograft growth, playing an important role at the tumor and at the microenvironment levels, the inhibition of PLD1 and PLD2 is necessary to reduce pancreatic carcinogenesis in KC mice and might represent a novel therapeutic target.
Inhibition of benzo[a]pyrene-induced DNA adduct in buccal cells of smokers by black raspberry lozenges.
Chen KM, Krebs NM, Sun YW … +8 more , Sun D, Liao J, Reinhart L, Krzeminski J, Amin S, Stoner G, Mallery SR, El-Bayoumy K
Carcinogenesis · 2025 Jan · PMID 39367810 · Full text
Using LC-MS/MS analysis we previously showed for the first time (Carcinogenesis 43:746-753, 2022) that levels of DNA damage induced by benzo[a]pyrene (B[a]P), an oral carcinogen and tobacco smoke (TS) constituent, were s...
Using LC-MS/MS analysis we previously showed for the first time (Carcinogenesis 43:746-753, 2022) that levels of DNA damage induced by benzo[a]pyrene (B[a]P), an oral carcinogen and tobacco smoke (TS) constituent, were significantly higher in buccal cells of smokers than those in nonsmokers; these results suggest the potential contribution of B[a]P in the development of oral squamous cell carcinoma (OSCC) in humans. Treating cancers, including OSCC, at late stages, even with improved targeted therapies, continues to be a major challenge. Thus interception/prevention remains a preferable approach for OSCC management and control. In previous preclinical studies, we and others demonstrated the protective effects of black raspberry (BRB) against carcinogen-induced DNA damage and OSCC. Thus, to translate preclinical findings, we tested the hypothesis in a Phase 0 clinical study that BRB administration reduces DNA damage induced by B[a]P in the buccal cells of smokers. After enrolling 27 smokers, baseline buccal cells were collected before the administration of BRB lozenges (5/day for 8 weeks, 1 gm BRB powder/lozenge) at baseline, at the middle and the end of BRB administration. The last samples were collected 4 weeks after BRB cessation (washout period). B[a]P-induced DNA damage (BPDE-N2-dG) was evaluated by LC-MS/MS. BRB administration resulted in a significant reduction in DNA damage: 26.3% at the midpoint (P = .01506) compared to baseline, 36.1% at the end of BRB administration (P = .00355), and 16.6% after BRB cessation (P = .007586). Our results suggest the potential benefits of BRB as a chemopreventive agent against the development of TS-initiated OSCC.
Ubiquitin-specific peptidase 49 promotes adenocarcinoma of the esophagogastric junction malignant progression via activating SHCBP1-β-catenin-GPX4 axis.
Ding Y, Liu Z, Dai X … +7 more , Ruan R, Zhong H, Wu Z, Yao Y, Chen J, Deng J, Xiong J
Carcinogenesis · 2025 Jan · PMID 39234990 · Publisher ↗
Adenocarcinoma of the esophagogastric junction (AEG) has received widespread attention because of its increasing incidence. However, the molecular mechanism underlying tumor progression remains unclear. Here, we report t...
Adenocarcinoma of the esophagogastric junction (AEG) has received widespread attention because of its increasing incidence. However, the molecular mechanism underlying tumor progression remains unclear. Here, we report that the downregulation of ubiquitin-specific peptidase 49 (USP49) promotes ferroptosis in OE33 and OE19 cells, thereby inhibiting cell proliferation in vitro and in vivo, whereas the overexpression of USP49 had the opposite effect. In addition, USP49 downregulation promoted AEG cell radiotherapy sensitivity. Moreover, overexpression of Glutathione PeroXidase 4 reversed the ferroptosis and proliferation inhibition induced by USP49 knockdown. Mechanistically, USP49 deubiquitinates and stabilizes Shc SH2-domain-binding protein 1, subsequently facilitating the entry of β-catenin into the nucleus to enhance Glutathione PeroXidase 4 transcriptional expression. Finally, high USP49 expression was correlated with shorter overall survival in patients with AEG. In summary, our findings identify USP49 as a novel regulator of ferroptosis in AEG cells, indicating that USP49 may be a potential therapeutic target in AEG.
HuR/miR-124-3p/VDR complex bridges lipid metabolism and tumor development in colorectal cancer.
Huang F, Bu L, Li M … +7 more , Wang Y, Zhang R, Shao Y, Lin K, Yang H, Zhao Q, Liu L
Carcinogenesis · 2025 Jan · PMID 39221893 · Publisher ↗
Maintaining a balanced lipid status to prevent lipotoxicity is of paramount importance in various tumors, including colorectal cancer (CRC). HuR, an RNA-binding protein family member, exhibits high expression in many can...
Maintaining a balanced lipid status to prevent lipotoxicity is of paramount importance in various tumors, including colorectal cancer (CRC). HuR, an RNA-binding protein family member, exhibits high expression in many cancers possibly because it regulates cell proliferation, migration, invasion, and lipid metabolism. However, the role of HuR in the regulation of abnormal lipid metabolism in CRC remains unknown. We found that HuR promotes vitamin D receptor (VDR) expression to ensure lipid homeostasis by increasing triglyceride (TG) and total cholesterol (TC) levels in CRC, thus confirming the direct binding of an overexpressed HuR to the CDS and 3'-UTR of Vdr, enhancing its expression. Concurrently, HuR can indirectly affect VDR expression by inhibiting miR-124-3p. HuR can suppress the expression of miR-124-3p, which binds to the 3'-UTR of Vdr, thereby reducing VDR expression. Additionally, a xenograft model demonstrated that targeting HuR inhibits VDR expression, blocking TG and TC formation, and hence mitigating CRC growth. Our findings suggest a regulatory relationship among HuR, miR-124-3p, and VDR in CRC. We propose that the HuR/miR-124-3p/VDR complex governs lipid homeostasis by impacting TG and TC formation in CRC, offering a potential therapeutic target for CRC prevention and treatment.
The BCL2-associated athanogene-3-Interferon-induced transmembrane protein 2 axis enhances pancreatic ductal adenocarcinoma growth via the Mitogen-activated protein kinase signaling pathway.
Wang P, Chen C, Lin K … +4 more , Zhang Y, Hu J, Zhu T, Wang X
Carcinogenesis · 2024 Dec · PMID 39210737 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy, exhibits escalating incidence and mortality rates, underscoring the urgent need for the identification of novel therapeutic targets and strategies. The...
Pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy, exhibits escalating incidence and mortality rates, underscoring the urgent need for the identification of novel therapeutic targets and strategies. The BCL2-associated athanogene-3 (BAG3) protein, a multifunctional regulator involved in various cellular processes, notably plays a crucial role in promoting tumor progression and acts as a potential "bridge" between tumors and the tumor microenvironment. In this study, we demonstrate that PDAC cells secrete BAG3 (sBAG3), which engages the interferon-induced transmembrane protein 2 (IFITM2) receptor to activate the mitogen-activated protein kinase signaling pathway, specifically enhancing phospho-extracellular regulated protein (pERK) activity, thereby propelling PDAC growth. Furthermore, our preliminary investigation into the effects of sBAG3 on co-cultured natural killer cells intriguingly discovered that sBAG3 diminishes natural killer cell cytotoxicity and active molecule expression. In conclusion, our findings confirm the pivotal role of the sBAG3-IFITM2 axis in fostering PDAC progression, highlighting the potential significance of sBAG3 as a dual therapeutic target for both tumor and immune cells.
Advanced glycation end products promote the progression of endometrial cancer via activating the RAGE/CHKA/PI3K/AKT signaling pathway.
Shu W, Hua T, Xin X … +8 more , Zhang J, Lin J, Shi R, Zhao R, Zhang W, Dong KJ, Wang H, Zhou X
Carcinogenesis · 2025 Jan · PMID 39180262 · Publisher ↗
Endometrial cancer (EC) is a common malignant tumor that is closely associated with metabolic disorders such as diabetes and obesity. Advanced glycation end products (AGEs) are complex polymers formed by the reaction of...
Endometrial cancer (EC) is a common malignant tumor that is closely associated with metabolic disorders such as diabetes and obesity. Advanced glycation end products (AGEs) are complex polymers formed by the reaction of reducing sugars with the amino groups of biomacromolecules, mediating the occurrence and development of many chronic metabolic diseases. Recent research has demonstrated that the accumulation of AGEs can affect the tumor microenvironment, metabolism, and signaling pathways, thereby affecting the malignant progression of tumors. However, the mechanism by which AGEs affect EC is unclear. Our research aimed to investigate how AGEs promote the development of EC through metabolic pathways and to explore their potential underlying mechanisms. Our experimental results demonstrated that AGEs upregulated the choline metabolism mediated by choline kinase alpha (CHKA) through the receptor for advanced glycation end products, activating the PI3K/AKT pathway and enhancing the malignant biological behavior of EC cells. Virtual screening and molecular dynamics simulation revealed that timosaponin A3 could target CHKA to inhibit AGE-induced progression of EC and that a newly discovered CHKA inhibitor could be a novel targeted inhibitor for the treatment of EC. This study provides new therapeutic strategies and contributes to the treatment of EC.
ETS1 deficiency in macrophages suppresses colorectal cancer progression by reducing the F4/80+TIM4+ macrophage population.
Cao Y, Guo A, Li M … +7 more , Ma X, Bian X, Chen Y, Zhang C, Huang S, Zhao W, Zhao S
Carcinogenesis · 2024 Oct · PMID 39162797 · Publisher ↗
Tumor-associated macrophages (TAMs) take on pivotal and complex roles in the tumor microenvironment (TME); however, their heterogeneity in the TME remains incompletely understood. ETS proto-oncogene 1 (ETS1) is a transcr...
Tumor-associated macrophages (TAMs) take on pivotal and complex roles in the tumor microenvironment (TME); however, their heterogeneity in the TME remains incompletely understood. ETS proto-oncogene 1 (ETS1) is a transcription factor that is mainly expressed in lymphocytes. However, its expression and immunoregulatory role in colorectal cancer (CRC)-associated macrophages remain unclear. In the study, the expression levels of ETS1 in CD68+ macrophages in the CRC microenvironment were significantly higher than those in matched paracarcinoma tissues. Importantly, ETS1 increased the levels of chemokines C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) in lipopolysaccharide-stimulated THP-1 cells. It also boosted the migration and invasion of CRC cells during the in vitro co-culture. In the ETS1 conditional knockout mouse model, ETS1 deficiency in macrophages ameliorated the histological changes in DSS-induced ulcerative colitis mouse models and prolonged the survival in an azomethane/dextran sodium sulfate (AOM/DSS)-induced CRC model. ETS1 deficiency in macrophages substantially inhibited tumor formation, reduced F4/80+TIM4+ macrophages in the mesenteric lymph nodes, and decreased CCL2 and CXCL10 protein levels in tumor tissues. Moreover, ETS1 deficiency in macrophages effectively prevented liver metastasis of CRC and reduced the infiltration of TAMs into the metastasis sites. Subsequent studies have indicated that ETS1 upregulated the expression of T-cell immunoglobulin mucin receptor 4 in macrophages through the signal transducer and activator of the transcription 1 signaling pathway activated by the autocrine action of CCL2/CXCL10. Collectively, ETS1 deficiency in macrophages potentiates antitumor immune responses by repressing CCL2 and CXCL10 expression, shedding light on potential therapeutic strategies for CRC.
ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.
Moreno P, Ohara Y, Craig AJ … +11 more , Liu H, Yang S, Dorsey TH, Zhang L, Panigrahi G, Cawley H, Azizian A, Gaedcke J, Ghadimi M, Hanna N, Hussain SP
Carcinogenesis · 2024 Nov · PMID 39136088 · Full text
Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative tra...
Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Our comprehensive analysis revealed that adrenoceptor alpha 2A (ADRA2A) was downregulated in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.
Allura Red AC is a xenobiotic. Is it also a carcinogen?
Hofseth LJ, Hebert JR, Murphy EA … +4 more , Trauner E, Vikas A, Harris Q, Chumanevich AA
Carcinogenesis · 2024 Oct · PMID 39129647 · Full text
Merriam-Webster and Oxford define a xenobiotic as any substance foreign to living systems. Allura Red AC (a.k.a., E129; FD&C Red No. 40), a synthetic food dye extensively used in manufacturing ultra-processed foods and t...
Merriam-Webster and Oxford define a xenobiotic as any substance foreign to living systems. Allura Red AC (a.k.a., E129; FD&C Red No. 40), a synthetic food dye extensively used in manufacturing ultra-processed foods and therefore highly prevalent in our food supply, falls under this category. The surge in synthetic food dye consumption during the 70s and 80s was followed by an epidemic of metabolic diseases and the emergence of early-onset colorectal cancer in the 1990s. This temporal association raises significant concerns, particularly given the widespread inclusion of synthetic food dyes in ultra-processed products, notably those marketed toward children. Given its interactions with key contributors to colorectal carcinogenesis such as inflammatory mediators, the microbiome, and DNA damage, there is growing interest in understanding Allura Red AC's potential impact on colon health as a putative carcinogen. This review discusses the history of Allura Red AC, current research on its effects on the colon and rectum, potential mechanisms underlying its impact on colon health, and provides future considerations. Indeed, although no governing agencies classify Allura Red AC as a carcinogen, its interaction with key guardians of carcinogenesis makes it suspect and worthy of further molecular investigation. The goal of this review is to inspire research into the impact of synthetic food dyes on colon health.
Intratumoral vitamin D signaling and lethal prostate cancer.
Vaselkiv JB, Shui IM, Grob ST … +7 more , Ericsson CI, Giovannucci I, Peng C, Finn SP, Mucci LA, Penney KL, Stopsack KH
Carcinogenesis · 2024 Oct · PMID 39120256 · Full text
High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D sig...
High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of transcriptionally upregulated (CYP27A1, CYP2R1, RXRA, RXRB, and VDR) and downregulated genes (CYP24A1 and DHCR7). We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n = 285). The gene score was downregulated in tumor tissue compared with tumor-adjacent histologically normal tissue of the same men. Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest versus lowest quartile: 0.46, 95% confidence interval: 0.21-0.99) in a dose-response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor.
Elevated expression of Golgi Transport 1B promotes the progression of cervical cancer by activating the NF-kappaB signaling pathway via interaction with TANK-Binding Kinase 1.
Sun Y, Peng Q, Wang R … +5 more , Yin Y, Mutailifu M, Hu L, Teng Y, Zhou Y
Carcinogenesis · 2025 Jan · PMID 39113410 · Publisher ↗
As a preventable disease, cervical cancer (cervical squamous cell carcinoma and endocervical adenocarcinoma-CESC) remains a tumor with high morbidity and mortality worldwide, underscoring the pressing need for effective...
As a preventable disease, cervical cancer (cervical squamous cell carcinoma and endocervical adenocarcinoma-CESC) remains a tumor with high morbidity and mortality worldwide, underscoring the pressing need for effective treatment strategies. This research identified Golgi transport 1B (GOLT1B) as a critical gene involved in the development of cervical cancer. Gene Expression Omnibus (GEO) datasets were investigated to determine the upregulation of GOLT1B in cervical cancer tissue compared with normal tissue. Besides, GOLT1B was found to predict poor prognosis in cervical cancer by utilizing Gene Expression Profiling Interactive Analysis (GEPIA). The functional assay indicated that GOLT1B promoted CESC viability and migration in vitro and in vivo. RNA sequencing results suggested that GOLT1B likely influenced the nuclear factor-kappaB (NF-κB) pathway. The subsequent western blot and dual luciferase reporter assay revealed the interaction between GOLT1B and TANK binding kinase 1 (TBK1), modulating the NF-κB pathway. More importantly, GOLT1B was also found to regulate immune cell infiltration, suggesting its potential role in the tumor microenvironment. In conclusion, GOLT1B promotes CESC progression via interaction with TBK1 and augmentation of NF-κB signaling-mediated cancer-associated inflammation, which provides us with a new approach to CESC target therapy.
Correction to: Epigenetic silencing of O6 -methylguanine DNA methyltransferase gene in NiS-transformed cells.
Carcinogenesis · 2024 Sep · PMID 39110894 · Publisher ↗
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Machine learning based on biological context facilitates the identification of microvascular invasion in intrahepatic cholangiocarcinoma.
Xu S, Wan M, Ye C … +4 more , Chen R, Li Q, Zhang X, Ruan J
Carcinogenesis · 2024 Oct · PMID 39086220 · Publisher ↗
Intrahepatic cholangiocarcinoma is a rare disease associated with a poor prognosis, primarily due to early recurrence and metastasis. An important feature of this condition is microvascular invasion (MVI). However, curre...
Intrahepatic cholangiocarcinoma is a rare disease associated with a poor prognosis, primarily due to early recurrence and metastasis. An important feature of this condition is microvascular invasion (MVI). However, current predictive models based on imaging have limited efficacy in this regard. This study employed a random forest model to construct a predictive model for MVI identification and uncover its biological basis. Single-cell transcriptome sequencing, whole exome sequencing, and proteome sequencing were performed. The area under the curve of the prediction model in the validation set was 0.93. Further analysis indicated that MVI-associated tumor cells exhibited functional changes related to epithelial-mesenchymal transition and lipid metabolism due to alterations in the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways. Tumor cells were also differentially enriched for the interleukin-17 signaling pathway. There was less infiltration of SLC30A1+ CD8+ T cells expressing cytotoxic genes in MVI-associated intrahepatic cholangiocarcinoma, whereas there was more infiltration of myeloid cells with attenuated expression of the major histocompatibility complex II pathway. Additionally, MVI-associated intercellular communication was closely related to the SPP1-CD44 and ANXA1-FPR1 pathways. These findings resulted in a brilliant predictive model and fresh insights into MVI.
CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma.
Li Z, Li X, Seebacher NA … +6 more , Liu X, Wu W, Yu S, Hornicek FJ, Huang C, Duan Z
Carcinogenesis · 2024 Oct · PMID 39082894 · Publisher ↗
Osteosarcoma (OS) is a bone malignant tumor affecting children, adolescents, and young adults. Currently, osteosarcoma is treated with chemotherapy regimens established over 40 years ago. The investigation of novel thera...
Osteosarcoma (OS) is a bone malignant tumor affecting children, adolescents, and young adults. Currently, osteosarcoma is treated with chemotherapy regimens established over 40 years ago. The investigation of novel therapeutic strategies for the treatment of osteosarcoma remains an important clinical need. Cyclin-dependent kinases (CDKs) have been considered promising molecular targets in cancer therapy. Among these, CDK12 has been shown to play a crucial role in the pathogenesis of malignancies, but its clinical significance and biological mechanisms in osteosarcoma remain unclear. In the present study, we aim to determine the expression and function of CDK12 and evaluate its prognostic and therapeutic value in metastatic osteosarcoma. We found that overexpression of CDK12 was associated with high tumor grade, tumor progression and reduced patient survival. The underlying mechanism revealed that knockdown of CDK12 expression with small interfering RNA or functional inhibition with the CDK12-targeting agent THZ531 effectively exhibited time- and dose-dependent cytotoxicity. Downregulation of CDK12 paused transcription by reducing RNAP II phosphorylation, interfered with DNA damage repair with increased γH2AX, and decreased cell proliferation through the PI3K-AKT pathway. This was accompanied by the promotion of apoptosis, as evidenced by enhanced Bax expression and reduced Bcl-xL expression. Furthermore, the CDK12 selective inhibitor THZ531 also hindered ex vivo 3D spheroid formation, growth of in vitro 2D cell colony, and prevented cell mobility. Our findings highlight the clinical importance of CDK12 as a potentially valuable prognostic biomarker and therapeutic target in metastatic osteosarcoma.
Enhancing carboplatin sensitivity in ovarian cancer cells by blocking the mercapturic acid pathway transporter.
Krishna BM, Ramisetty SK, Garg P … +7 more , Mohanty A, Wang E, Horne D, Awasthi S, Kulkarni P, Salgia R, Singhal SS
Carcinogenesis · 2024 Sep · PMID 39051454 · Publisher ↗
Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione-electrophile conjugates and xenobiotic toxins. Its increased presence in mali...
Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione-electrophile conjugates and xenobiotic toxins. Its increased presence in malignant cells, especially in cancer, emphasizes its crucial antiapoptotic function. This is achieved by selectively regulating the cellular levels of proapoptotic oxidized lipid byproducts. Suppressing the progression of tumors in human xenografts can be achieved by effectively inhibiting RLIP, a transporter in the mercapturic acid pathway, without involving chemotherapy. Utilizing ovarian cancer (OC) cell lines (MDAH2774, OVCAR4, and OVCAR8), we observed that agents targeting RLIP, such as RLIP antisense and RLIP antibodies, not only substantially impeded the viability of OC cells but also remarkably increased their sensitivity to carboplatin. To delve further into the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin, we conducted investigations in both cell culture and xenografts of OC cells. The outcomes revealed that RLIP depletion via phosphorothioate antisense led to rapid and sustained remissions in established subcutaneous human ovary xenografts. Furthermore, RLIP inhibition by RLIP antibodies exhibited comparable efficacy to antisense and enhanced the effectiveness of carboplatin in MDAH2774 OC xenografts. These investigations underscore RLIP as a central carrier crucial for supporting the survival of cancer cells, positioning it as a suitable focus for cancer treatment.
Stem cells, Notch-1 signaling, and oxidative stress: a hellish trio in cancer development and progression within the airways. Is there a role for natural compounds?
Chiappara G, Di Vincenzo S, Cascio C … +1 more , Pace E
Carcinogenesis · 2024 Sep · PMID 39046986 · Full text
Notch-1 signaling plays a crucial role in stem cell maintenance and in repair mechanisms in various mucosal surfaces, including airway mucosa. Persistent injury can induce an aberrant activation of Notch-1 signaling in s...
Notch-1 signaling plays a crucial role in stem cell maintenance and in repair mechanisms in various mucosal surfaces, including airway mucosa. Persistent injury can induce an aberrant activation of Notch-1 signaling in stem cells leading to an increased risk of cancer initiation and progression. Chronic inflammatory respiratory disorders, including chronic obstructive pulmonary disease (COPD) is associated with both overactivation of Notch-1 signaling and increased lung cancer risk. Increased oxidative stress, also due to cigarette smoke, can further contribute to promote cancer initiation and progression by amplifying inflammatory responses, by activating the Notch-1 signaling, and by blocking regulatory mechanisms that inhibit the growth capacity of stem cells. This review offers a comprehensive overview of the effects of aberrant Notch-1 signaling activation in stem cells and of increased oxidative stress in lung cancer. The putative role of natural compounds with antioxidant properties is also described.
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