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Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin–proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.

Tumor immune microenvironment (TIME) and its indications for lung cancer patient prognosis and therapeutic response have become new hotspots in cancer research in recent years. Tumor cells, immune cells, various regulatory factors, and their interactions in the TIME have been suggested to commonly influence lung cancer development and therapeutic outcome. The heterogeneity of TIME is composed of dynamic immune-related components, including various cancer cells, immune cells, cytokine/chemokine environments, cytotoxic activity, or immunosuppressive factors. The specific composition of cell subtypes may facilitate or hamper the response to immunotherapy and influence patient prognosis. Various markers have been found to stratify the patient prognosis or predict the therapeutic outcome. In this article, we systematically reviewed the recent advancement of TIME studies in lung adenocarcinoma (LUAD) using single-cell RNA sequencing (scRNA-seq) techniques, with specific focuses on the roles of TIME in LUAD development, TIME heterogeneity, indications of TIME in patient prognosis and therapeutic response during immunotherapy and drug resistance. The main findings in TIME heterogeneity and relevant markers or models for prognosis stratification and response prediction have been summarized. We hope that this review provides an overview of TIME status in LUAD and an inspiration for future development of strategies and biomarkers in LUAD treatment.

Geraniol is a dietary monoterpene alcohol that is found in the essential oils of aromatic plants. To date, experimental evidence supports the therapeutic or preventive effects of geraniol on different types of cancer, such as breast, lung, colon, prostate, pancreatic, and hepatic cancer, and has revealed the mechanistic basis for its pharmacological actions. In addition, geraniol sensitizes tumor cells to commonly used chemotherapy agents. Geraniol controls a variety of signaling molecules and pathways that represent tumor hallmarks; these actions of geraniol constrain the ability of tumor cells to acquire adaptive resistance against anticancer drugs. In the present review, we emphasize that geraniol is a promising compound or chemical moiety for the development of a safe and effective multi-targeted anticancer agent. We summarize the current knowledge of the effects of geraniol on target molecules and pathways in cancer cells. Our review provides novel insight into the challenges and perspectives with regard to geraniol research and to its application in future clinical investigation.

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed. Since the discovery of the signal transducer and activator of transcription 3 (STAT3) in 1994, the STAT3 pathway has been proven to play a pivotal role in cancer initiation, progression, and metastasis. This review summarizes the mechanisms of the STAT3 pathway regulation and the relationship between the STAT3 pathway and cancer hallmarks. The emerging development of the STAT3 pathway inhibitors, novel drug delivery systems, and perspective on the overall utility of the STAT3 pathway are also introduced.

The Bhas 42 cell transformation assay (Bhas 42 CTA) is the first Organization for Economic Cooperation and Development (OECD)-certificated method used as a specific tool for the detection of the cell-transformation potential of tumor-promoting compounds, including non-genotoxic carcinogens (NGTxCs), as separate from genotoxic carcinogens. This assay offers the great advantage of enabling the phenotypic detection of oncotransformation. A key benefit of using the Bhas 42 CTA in the study of the cell-transformation mechanisms of tumor-promoting compounds, including non-genotoxic carcinogens, is that the cell-transformation potential of the chemical can be detected directly without treatment with a tumor-initiating compound since Bhas 42 cell line was established by transfecting the v-Ha-ras gene into a mouse fibroblast cloned cell line. Here, we analyzed the gene expression over time, using DNA microarrays, in Bhas 42 cells treated with the tumor-promoting compound 12-O-tetradecanoylphorbol-13-acetate (TPA), and NGTxC, with a total of three repeat experiments. This is the first paper to report on gene expression over time during the process of cell transformation with only a tumor-promoting compound. Pathways that were activated or inactivated during the process of cell transformation in the Bhas 42 cells treated with TPA were related not only directly to RAS but also to various pathways in the hallmarks of cancer.

Background: Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial. Methods: Between March 2017 and September 2022, the patients diagnosed as stages I–IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan–Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models. Results: A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS/BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36–5.12; p = 0.0091). Conclusion: In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I–III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.

Bladder cancer (BC) poses a significant health challenge, particularly in metastatic cases, where the prognosis is unfavorable and therapeutic options are limited. Poly ADP-ribose polymerase (PARP) inhibitors have gained approval for use in various cancer types, but their application in BC remains controversial, despite the notable prevalence of DNA damage response alterations in advanced or metastatic urothelial carcinomas. In this report, we describe a 66-year-old heavy-smoking female diagnosed with muscle-invasive BC. She underwent multiple rounds of chemotherapy and radiation, yet her disease remained poorly controlled, leading to metastasis in the left obturator internus muscle. Comprehensive genomic profiling through FoundationOne® Liquid CDx, examining a 324-gene panel using circulating tumor DNA from blood samples, revealed a pathogenic ATM gene alteration (p.Q654fs*10, c.1960delC), suggesting potential eligibility for PARP inhibitor therapy. Remarkably, the patient achieved a complete response to talazoparib, prompting an optimal investigation into BC candidates for this promising therapy. Plain language summary A new hope for advanced bladder cancer treatment: a case study on the success of PARP inhibitors Bladder cancer is a significant health problem, particularly when it spreads to other parts of the body. The outcome for these advanced cases is often poor and treatment options are limited. One type of treatment, called PARP inhibitors, has shown success in treating other types of cancer, but its use in bladder cancer is still under investigation. This article presents the case of a 66-year-old heavy-smoker woman who was diagnosed with an aggressive form of bladder cancer. Despite several rounds of chemotherapy and radiation, her cancer was not well-controlled and spread to a hip muscle. A detailed genetic analysis revealed specific alterations that suggested she might benefit from treatment with a PARP inhibitor. This type of treatment works by blocking a protein that cancer cells need to repair their DNA, causing the cancer cells to die. The patient was treated with a PARP inhibitor called talazoparib and her cancer completely disappeared with this treatment. This positive response highlights the potential of PARP inhibitors as a promising treatment for bladder cancer, especially in patients who don’t respond to conventional treatments and whose cancer has specific genetic changes. Our study also provides an overview of clinical trials evaluating PARP inhibitors in bladder cancer and summaries reported bladder cancer cases in the literature showing a good response to PARP inhibitors, along with their respective genetic alterations. In conclusion, this case study contributes to the growing understanding of personalized medicine, where treatment is tailored to the specific genetic mutations of each patient’s cancer. It emphasizes the importance of identifying bladder cancer patients who could benefit most from PARP inhibitor therapy, offering a potential lifeline for those who haven’t responded to initial treatment.

The “hallmarks of cancer” concept provides a valuable framework for understanding fundamental organizing principles common to various cancers. However, without a consensus gene set for cancer hallmarks, data comparison and integration result in diverse biological interpretations across studies. Therefore, we aimed to form a consensus cancer hallmark gene set by merging data from available mapping resources and establishing a framework for mining these gene sets. By consolidating data from seven projects, 6763 genes associated with 10 cancer hallmarks were identified. A cancer hallmarks enrichment analysis was performed for prognostic genes associated with overall survival across 12 types of solid tumors. “Tissue invasion and metastasis” was most prominent in cancers of the stomach (P = 2.2 × 10−11), pancreas (P = 4.2 × 10−9), bladder (P = 3.3 × 10−8), and ovaries (P = 0.0007), aligning with their heightened potential to spread. “Sustained angiogenesis” was most prominent in squamous cell carcinomas of the lung (P = 2.5 × 10−7), while “genome instability” showed strong enrichment in lung adenocarcinomas (LUADs) (P = 1.5 × 10−8) and cancers of the liver (P = 5.5 × 10−10), pancreas (P = 2.1 × 10−5), and kidney (P = 0.018). Pancreatic cancers displayed the highest enrichment of hallmarks, emphasizing the disease's complexity, while in melanomas and cancers of the liver, prostate, and kidney, a single hallmark was enriched among the prognostic markers of survival. Additionally, an online tool (www.cancerhallmarks.com) that allows the identification of cancer-associated hallmarks from new gene sets was established. In summary, our aim of establishing a consensus list of cancer hallmark genes was achieved. Furthermore, the analysis of survival-associated genes revealed a unique pattern of hallmark enrichment with potential pharmacological implications in different tumor types. [Display omitted] •A consensus gene set for cancer hallmarks reduces complications in data comparison and integration.•Data from seven projects were consolidated, and genes tied to ten cancer hallmarks were identified.•An online tool was created for overrepresentation analysis of cancer hallmarks from gene sets.•This analysis may aid in identifying potential drug targets linked to cancer hallmarks.

Introduction: DNA ploidy (P), stroma fraction (S), and nucleotyping (N) collectively known as PSN, have proven prognostic accuracy in stage II colorectal cancer (CRC). However, few studies have reported on the prognostic value of the PSN panel in stage III colon cancer patients receiving capecitabine and oxaliplatin adjuvant chemotherapy. Objectives: This study aimed to validate PSN’s prognostic impact on stage III colon cancer, identifying candidates for optimized adjuvant chemotherapy duration. Design: A retrospective analysis was conducted on a cohort of stage III colon cancer patients from April 2008 to June 2020. Methods: Postoperative pathological samples from stage III colon cancer patients who underwent radical surgery and postoperative adjuvant chemotherapy at Sun Yat-sen University Cancer Center were retrospectively collected. Automated digital imaging assessed PSN, categorizing risk groups. Kaplan–Meier, Cox regression, and time-dependent receiver operating characteristic analysis compared model validity. Results: Significant differences in 5-year disease-free survival (DFS) and overall survival (OS) were noted among PSN-based low-, moderate-, and high-risk groups (DFS: 92.10% versus 83.62% versus 79.80%, p = 0.029; OS: 96.69% versus 93.99% versus 90.12%, p = 0.016). PSN emerged as an independent prognostic factor for DFS [hazard ratio (HR) = 1.409, 95% confidence interval (CI): 1.002–1.981, p = 0.049] and OS (HR = 1.720, 95% CI: 1.127–2.624, p = 0.012). The PSN model, incorporating perineural invasion and tumor location, displayed superior area under the curve for 5-year (0.692 versus 0.553, p = 0.020) and 10-year (0.694 versus 0.532, p = 0.006) DFS than TNM stage. In the PSN high-risk group, completing eight cycles of adjuvant chemotherapy significantly improved 5-year DFS and OS compared to four to seven cycles (DFS: 89.43% versus 71.52%, p = 0.026; OS: 96.77% versus 85.46%, p = 0.007). Conclusion: The PSN panel effectively stratifies stage III colon cancer, aiding in optimized adjuvant chemotherapy duration determination.

Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system. Complex multicellularity, and the cooperation underlying it, has evolved independently multiple times. We review the existing literature on cancer and cancer-like phenomena across life, not only focusing on complex multicellularity but also reviewing cancer-like phenomena across the tree of life more broadly. We find that cancer is characterized by a breakdown of the central features of cooperation that characterize multicellularity, including cheating in proliferation inhibition, cell death, division of labour, resource allocation and extracellular environment maintenance (which we term the five foundations of multicellularity). Cheating on division of labour, exhibited by a lack of differentiation and disorganized cell masses, has been observed in all forms of multicellularity. This suggests that deregulation of differentiation is a fundamental and universal aspect of carcinogenesis that may be underappreciated in cancer biology. Understanding cancer as a breakdown of multicellular cooperation provides novel insights into cancer hallmarks and suggests a set of assays and biomarkers that can be applied across species and characterize the fundamental requirements for generating a cancer.