Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities.

Hepatocellular carcinoma (HCC) is one of the most common cancers with a relatively high cancer-related mortality. The uncontrolled proliferation of HCC consumes a significant amount of oxygen, causing the development of a hypoxic tumor microenvironment (TME). Hypoxia-inducible factors (HIFs), crucial regulators in the TME, activate several cancer hallmarks leading to the hepatocarcinogenesis of HCC and resistance to current therapeutics. As such, HIFs and their signaling pathways have been explored as potential therapeutic targets for the future management of HCC. This review discusses the current understanding of the structure and function of HIFs and their complex relationship with the various cancer hallmarks. To address tumor hypoxia, this review provides an insight into the various potential novel therapeutic agents for managing HCC, such as hypoxia-activated prodrugs, HIF inhibitors, nanomaterials, antisense oligonucleotides, and natural compounds, that target HIFs/hypoxic signaling pathways in HCC. Because of HCC's relatively high incidence and mortality rates in the past decades, greater efforts should be put in place to explore novel therapeutic approaches to improve the outcome for HCC patients.

The role of tumor-derived extracellular vesicles containing noncoding RNAs in mediating immune cell function and its implications from bench to bedside.

Extracellular vesicles (EVs) are membrane-encapsulated vesicles released by almost all cell types, which participate in intercellular communication by delivering different types of molecular cargoes, such as non-coding RNAs (ncRNAs). Accumulating evidence suggests that tumor-derived EVs act as a bridge for intercellular crosstalk between tumor cells and surrounding cells, including immune cells. Tumor-derived EVs containing ncRNAs (TEV-ncRNAs) mediate intercellular crosstalk to manipulate immune responses and affect the malignant phenotypes of cancer cells. In this review, we summarize the double-edged roles and the underlying mechanisms of TEV-ncRNAs in regulating innate and adaptive immune cells. We also highlight the advantages of using TEV-ncRNAs in liquid biopsies for cancer diagnosis and prognosis. Moreover, we outline the use of engineered EVs to deliver ncRNAs and other therapeutic agents for cancer therapy.

Inhibitory Potential of Resveratrol in Cancer Metastasis: From Biology to Therapy.

Cancer metastasis is a significant challenge in cancer treatment, and most existing drugs are designed to inhibit tumor growth but are often ineffective in treating metastatic cancer, which is the leading cause of cancer-related deaths. Resveratrol, a polyphenol found in grapes, berries, and peanuts, has shown potential in preclinical studies as an anticancer agent to suppress metastasis. However, despite positive results in preclinical studies, little progress has been made in clinical trials. To develop resveratrol as an effective anticancer agent, it is crucial to understand its cellular processes and signaling pathways in tumor metastasis. This review article evaluates the current state and future development strategies of resveratrol to enhance its potency against cancer metastasis within its therapeutic dose. In addition, we critically evaluate the animal models used in preclinical studies for cancer metastasis and discuss novel techniques to accelerate the translation of resveratrol from bench to bedside. The appropriate selection of animal models is vital in determining whether resveratrol can be further developed as an antimetastatic drug in cancer therapy.

FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites.

Rationale: Metastasis is a complex process with a molecular underpinning that remains unclear. We hypothesize that cargo proteins conducted by extracellular vesicles (EVs) released from tumors may confer growth and metastasis potential on recipient cells. Here, we report that a cytokine-like secreted protein, FAM3C, contributes to late-stage lung tumor progression. Methods: EV protein profiling was conducted with an unbiased proteomic mass spectrometry analysis on non-small cell lung cancer (NSCLC) and normal lung fibroblast cell lines. Expression of FAM3C was confirmed in a panel of NSCLC cell lines, and correlated to the invasive and metastatic potentials. Functional phenotype of endogenous FAM3C and tumor-derived EVs (TDEs) were further investigated using various biological approaches in RNA and protein levels. Metastasis potential of TDEs secreted by FAM3C-overexpressing carcinoma cells was validated in mouse models. Results: Transcriptomic meta-analysis of pan-cancer datasets confirmed the overexpression of FAM3C - a gene encoding for interleukin-like EMT inducer (ILEI) - in NSCLC tumors, with strong association with poor patient prognosis and cancer metastasis. Aberrant expression of FAM3C in lung carcinoma cells enhances cellular transformation and promotes distant lung tumor colonization. In addition, higher FAM3C concentrations were detected in EVs extracted from plasma samples of NSCLC patients compared to those of healthy subjects. More importantly, we defined a hitherto-unknown mode of microenvironmental crosstalk involving FAM3C in EVs, whereby the delivery and uptake of FAM3C via TDEs enhances oncogenic signaling - in recipient cells that phenocopies the cell-endogenous overexpression of FAM3C. The oncogenicity transduced by FAM3C is executed via a novel interaction with the Ras-related protein RalA, triggering the downstream activation of the Src/Stat3 signaling cascade. Conclusions: Our study describes a novel mechanism for FAM3C-driven carcinogenesis and shed light on EV FAM3C as a driver for metastatic lung tumors that could be exploited for cancer therapeutics.

Hypoxia-Induced circRNAs in Human Diseases: From Mechanisms to Potential Applications.

Circular RNAs (circRNAs) are a special class of endogenous RNAs characterized by closed loop structures lacking 5' to 3' polarity and polyadenylated tails. They are widely present in various organisms and are more stable and conserved than linear RNAs. Accumulating evidence indicates that circRNAs play important roles in physiology-related processes. Under pathological conditions, hypoxia usually worsens disease progression by manipulating the microenvironment for inflammation and invasion through various dysregulated biological molecules. Among them, circRNAs, which are involved in many human diseases, including cancer, are associated with the overexpression of hypoxia-inducible factors. However, the precise mechanisms of hypoxic regulation by circRNAs remain largely unknown. This review summarizes emerging evidence regarding the interplay between circRNAs and hypoxia in the pathophysiological changes of diverse human diseases, including cancer. Next, the impact of hypoxia-induced circRNAs on cancer progression, therapeutic resistance, angiogenesis, and energy metabolism will be discussed. Last, but not least, the potential application of circRNAs in the early detection, prognosis, and treatment of various diseases will be highlighted.

Noncoding RNAs of Extracellular Vesicles in Tumor Angiogenesis: From Biological Functions to Clinical Significance.

Extracellular vesicles (EVs) act as multifunctional regulators of intercellular communication and are involved in diverse tumor phenotypes, including tumor angiogenesis, which is a highly regulated multi-step process for the formation of new blood vessels that contribute to tumor proliferation. EVs induce malignant transformation of distinct cells by transferring DNAs, proteins, lipids, and RNAs, including noncoding RNAs (ncRNAs). However, the functional relevance of EV-derived ncRNAs in tumor angiogenesis remains to be elucidated. In this review, we summarized current research progress on the biological functions and underlying mechanisms of EV-derived ncRNAs in tumor angiogenesis in various cancers. In addition, we comprehensively discussed the potential applications of EV-derived ncRNAs as cancer biomarkers and novel therapeutic targets to tailor anti-angiogenic therapy.

Systematic Review: Guideline-Based Approach for the Management of Asthma and Subtypes via Chinese Medicine.

BACKGROUND: Asthma is a chronic condition that results in the inflammation and narrowing of airways, often clinically presenting as wheeze and shortness of breath. Little is known of the mechanisms of action (MOA) of herbs used to treat asthma. The aim of this study is to review existing data regarding known MOA of traditional Chinese medicine which will aid in the understanding of possible interactions between Western drugs and Chinese herbs as well as the standardization of management via a proposed guideline to improve patient safety and possible synergism in the long term. METHODS: We searched through 5 databases for commonly prescribed herbs and formulas for asthma and narrowed down the search to identify the underlying MOA of individual herbs that could specifically target asthma symptoms. We included studies that stated the MOA of individual herbs when used for treating symptoms of asthma, excluding them if they are described as part of a formula. RESULTS: A total of 26 herbs commonly prescribed for asthma with known mechanism of action were identified. Herbs used for asthma were found to have similar MOA as that for drugs. Based on existing GINA guidelines, a guideline is proposed which includes a total of 5 steps depending on the severity of asthma and the herbs' MOA. 16 formulas were subsequently identified for the management of asthma, which consist of 12 "stand-alone" and 4 "add-on" formulas. "Stand-alone" formulas used independently for asthma generally follow the GINA guidelines but do not proceed beyond step 3. These formulas consist mainly of beta-agonist and steroid-like effects. "Add-on" formulas added as adjunct to "stand-alone" formulas, however, mainly act on T helper cells or have steroid-like effects. CONCLUSION: Through the understanding of MOA of herbs and their respective formulas, it will ensue greater patient safety and outcomes.

A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma.

c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to interact with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.

Integration of Antiangiogenic Therapy with Cisplatin and Gemcitabine Chemotherapy in Patients with Nasopharyngeal Carcinoma.

PURPOSE: Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC. PATIENTS AND METHODS: Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation. RESULTS: Complete metabolic response (mCR) by whole body 18FDG PET was highest in arm C (significant difference in four groups Fisher exact test P = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18-67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity. CONCLUSIONS: Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.