Zhaoguo Liu

Dll4-Notch signaling in regulation of tumor angiogenesis

Abstract Tumor angiogenesis is a complex process and involves the tight interplay of tumor cells, endothelial cells, phagocytes and their secreted factors, which may act as promoters or inhibitors of angiogenesis. Many signaling pathways involved in these processes such as vascular endothelial growth factor (VEGF), fibroblast growth factors, Wnt and mTOR signaling pathway. Though research has confirmed that VEGF can play an important role in tumor angiogenesis, and has designed a lot of drugs that target VEGF, both experimental and clinical studies showed that these pathways mentioned above including VEGF did not play key roles in tumor angiogenesis. With the deepening of the research, people find that of all the signaling pathways involved in tumor angiogenesis, Notch signaling is the most notable one and plays crucial role in tumor angiogenesis. It was previously recognized that the Notch signaling plays a key role only in physiological angiogenesis such as development, wound healing and pregnancy. However, an increasing number of studies have proved that Notch signaling is also involved in pathological angiogenesis such as tumor angiogenesis and plays a critical role in these processes. More importantly, compared to resistance caused by anti-VEGF or other signaling pathways, experimental evidence revealed that Notch was involved in anticancer drug resistance, indicating that targeting Notch could be a novel therapeutic approach to the treatment for cancer by overcoming drug resistance of cancer cells. More recently, research has demonstrated that Notch ligands Delta-like 4 (Dll4) plays a key role in tumor angiogenesis. Data show that Dll4 functions as a negative regulator of tumor angiogenesis and is upregulated in tumor vasculature. This review focus on recent insights into Dll4-Notch signaling in tumor angiogenesis and its mechanisms, which may be utilized for a potential pharmacological use as a target for anti-angiogenic cancer therapy.

Antimetastatic Therapies of the Polysulfide Diallyl Trisulfide against Triple-Negative Breast Cancer (TNBC) via Suppressing MMP2/9 by Blocking NF-κB and ERK/MAPK Signaling Pathways

Background Migration and invasion are two crucial steps of tumor metastasis. Blockage of these steps may be an effective strategy to reduce the risk. The objective of the present study was to investigate the effects of diallyl trisulfide (DATS), a natural organosulfuric compound with most sulfur atoms found in garlic, on migration and invasion in triple negative breast cancer (TNBC) cells. Molecular mechanisms underlying the anticancer effects of DATS were further investigated. Methods and Results MDA-MB-231 cells and HS 578t breast cancer cells were treated with different concentrations of DATS. DATS obviously suppressed the migration and invasion of two cell lines and changed the morphological. Moreover, DATS inhibited the mRNA/protein/ enzymes activities of MMP2/9 via attenuating the NF-κB pathway. DATS also inhibited ERK/MAPK rather than p38 and JNK. Conclusion DATS inhibits MMP2/9 activity and the metastasis of TNBC cells, and emerges as a potential anti-cancer agent. The inhibitory effects are associated with down-regulation of the transcriptional activities of NF-κB and ERK/MAPK signaling pathways.

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

Pyruvate kinase isozyme type M2(PKM2) was first found in hepatocellular carcinoma(HCC), and its expression has been thought to correlate with prognosis. A large number of studies have demonstrated that epithelial-mesenchymal transition (EMT) is a crucial event in hepatocellular carcinoma (HCC) and associated metastasis, resulting in enhanced malignancy of HCC. However, the roles of PKM2 in HCC EMT and metastasis remain largely unknown. The present study aimed to determine the effects of PKM2 in EGF-induced HCC EMT and elucidate the molecular mechanisms in vitro. Our results showed that EGF promoted EMT in HCC cell lines as evidenced by altered morphology, expression of EMT-associated markers, and enhanced invasion capacity. Furthermore, the present study also revealed that nuclear translocation of PKM2, which is regulated by ERK pathway, regulated β-catenin-TCF/LEF-1 transcriptional activity and associated EMT in HCC cell lines. These discoveries provide evidence of novel roles of PKM2 in the progression of HCC and potential therapeutic target for advanced cases.

Cancer-promoting effect of capsaicin on DMBA/TPA-induced skin tumorigenesis by modulating inflammation, Erk and p38 in mice.

Epidemiologic and animal studies revealed that capsaicin (8-methyl-N-vanillyl-6-noneamide) can act as a carcinogen or cocarcinogen. However, the influence of consumption of capsaicin-containing foods or vegetables on skin cancer patients remains largely unknown. In the present study, we demonstrated that capsaicin has a cocarcinogenic effect on 9, 10-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis. Our results showed that topical application of capsaicin on the dorsal skin of DMBA-initiated and TPA-promoted mice could significantly accelerate tumor formation and growth and induce more and larger skin tumors than the model group (DMBA + TPA). Moreover, capsaicin could promote TPA-induced skin hyperplasia and tumor proliferation. Mechanistic study found that inflammation-related factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were highly elevated by pretreatment with capsaicin, suggesting an inflammation-dependent mechanism. Furthermore, mice that were administered capsaicin exhibited significant up-regulation of phosphorylation of nuclear factor kappaB (NF-κB), Erk and p38 but had no effect on JNK. Thus, our results indicated that inflammation, Erk and P38 collectively played a crucial role in cancer-promoting effect of capsaicin on carcinogen-induced skin cancer in mice.

Chemopreventive efficacy of menthol on carcinogen-induced cutaneous carcinoma through inhibition of inflammation and oxidative stress in mice

Inflammation and oxidative stress have been implicated in various pathological processes including skin tumorigenesis. Skin cancer is the most common form of cancer responsible for considerable morbidity and mortality, the treatment progress of which remains slow though. Therefore, chemoprevention and other strategies are being considered. Menthol has shown high anticancer activity against various human cancers, but its effect on skin cancer has never been evaluated. We herein investigated the chemopreventive potential of menthol against 9,10-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation, oxidative stress and skin carcinogenesis in female ICR mice. Pretreatment with menthol at various doses significantly suppressed tumor formation and growth, and markedly reduced tumor incidence and volume. Moreover, menthol inhibited TPA-induced skin hyperplasia and inflammation, and significantly suppressed the expression of cyclooxygenase-2 (COX-2). Furthermore, pretreatment with menthol inhibited the formation of reactive oxygen species and affected the activities of a battery of antioxidant enzymes in the skin. The expressions of NF-κB, Erk and p38 were down-regulated by menthol administration. Thus, inflammation and oxidative stress collectively played a crucial role in the chemopreventive efficacy of menthol on the murine skin tumorigenesis.

Prophylaxis of Diallyl Disulfide on Skin Carcinogenic Model via p21-dependent Nrf2 stabilization

Cancer prevention through intake of biologically active natural products appears to be an accessible way to reduce the risk of cancer. Diallyl disulfide (DADS), a major garlic derivative, has exhibited potential role in cancer therapy. The study is aimed to evaluate the prophylactic effect of DADS in chemically induced mouse skin carcinogenesis and investigate the molecular targets mediated by DADS. Two-stage chemically induced carcinogenesis model by cutaneous application of DMBA and subsequent TPA was established to study the prophylactic effect of DADS. As a result, we observed that DADS dose-dependently attenuated skin tumor incidence and multiplicity in the model mice, which was related to the up-regulation of a bunch of antioxidant enzymes activities and the nuclear accumulation of Nrf2. Furthermore, we developed skin carcinogenesis in Nrf2 knockout mice which could reverse the activity of DADS. Finally, we uncovered the underlying mechanism that DADS promoted the endogenous interaction between p21 and Nrf2, which was critical for impairing the Keap1-mediated degradation of Nrf2. Based on the results, we concluded that DADS was a promising cancer chemoprevention agent and suggested a garlic-rich diet might be beneficial to reduce the cancer risk in our daily life.

TRPM8: a potential target for cancer treatment.

Abstract Transient receptor potential (TRP) cation channel superfamily plays critical roles in variety of processes, including temperature perception, pain transduction, vasorelaxation, male fertility, and tumorigenesis. One of seven families within the TRP superfamily of ion channels, the melastatin, or TRPM family comprises a group of eight structurally and functionally diverse channels. Of all the members of TRPM subfamily, TRPM8 is the most notable one. A lot of literatures have demonstrated that transient receptor potential melastatin 8 (TRPM8) could perform a myriad of functions in vertebrates and invertebrates alike. In addition to its well-known function in cold sensation, TRPM8 has an emerging role in a variety of biological systems, including thermoregulation, cancer, bladder function, and asthma. Recent studies have shown that TRPM8 is necessary to the initiation and progression of tumors, and the aberrant expression of TRPM8 was found in varieties of tumors, such as prostate tumor, melanoma, breast adenocarcinoma, bladder cancer, and colorectal cancer, making it a novel molecular target potentially useful in the diagnosis and treatment of cancer. This review outlines our current understanding on the role of TRPM8 in occurrence and development of different kinds of tumor and also includes discussion about the regulation of TRPM8 during carcinogenesis as well as therapeutic potential of targeting TRPM8 in tumor, which may be utilized for a potential pharmacological use as a target for anti-cancer therapy.

Cryptotanshinone, a novel tumor angiogenesis inhibitor, destabilizes tumor necrosis factor-α mRNA via decreasing nuclear–cytoplasmic translocation of RNA-binding protein HuR

Cryptotanshinone (CT), one major lipophilic component isolated from Salvia miltiorrhiza Bunge, has shown to possess chemopreventive properties against various types of cancer cells. In this study, CT was shown to be a potent anti‐angiogenic agent in zebrafish, and mouse models and could limit tumor growth by inhibiting tumor angiogenesis. We further found that CT could inhibit the proliferation, migration, angiogenic sprouting, and tube formation of HUVECs. In addition, we demonstrated that CT could lower the level of TNF‐α due to the destabilization of TNF‐α mRNA, which associated with regulating 3′‐untranslated region (3′‐UTR) of TNF‐α and preventing the translocation of RNA binding protein, HuR, from the nucleus to the cytoplasm. Moreover, the underlying mechanism responsible for the regulation in angiogenesis by CT was partially related to the suppression of NF‐κB, and STAT3 activity. Based on the abilities of CT in targeting tumor cells, inhibiting angiogenesis, and destroying tumor vasculature, CT is worthy of further investigation for preventive, and therapeutic purposes in cancer.

The angiogenic responses induced by release of angiogenic proteins from tumor cell-activated platelets are regulated by distinct molecular pathways

There is mounting evidence that tumor angiogenesis can be regulated by platelets (Plts), which serve as major sources and delivery vehicles of many proangiogenic cytokines including transforming growth factor‐β and vascular endothelial growth factor. Although considerable progress has been made in understanding the role for Plt secretion in tumor angiogenesis, very little is known about the precise mechanisms underlying cancer cell induction of Plt granule release. Here, we demonstrated that nonsmall cell lung cancer (NSCLC) cells directly induced Plt secretion of several angiogenic regulatory cytokines that promoted angiogenesis in concert. Moreover, we discovered that these Plt‐derived angiogenesis modulators were regulated by different molecular pathways and could be largely inhibited by combination of multiple signaling inhibitors. Our present studies indicated that manipulation of Plt secretion of angiogenic cytokines without compromising hemostatic functions could provide a novel option for management of tumor angiogenesis and metastasis in NSCLC patients with thrombocytosis.

Diallyl Trisulfides, a natural histone deacetylase inhibitor, attenuate HIF-1α synthesis and decreases Breast Cancer Metastasis†

Intratumoral hypoxia promotes the distant metastasis of cancer subclones. The clinical expression level of hypoxia‐inducible factor‐1α (HIF‐1α) reflects the prognosis of a variety of cancers, especially breast cancer. Histone deacetylase (HDAC) inhibitors can target HIF‐1α protein due to von Hippel‐Lindau (VHL) protein‐dependent degradation. Dietary organosulfur compounds, such as those in garlic, have been reported as HDAC inhibitors. The effects of diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) on the ratio of firefly/Renilla luciferase activity in hypoxic MDA‐MB‐231 cells were determined. The mRNA expressions of HIF‐1α target genes ANGPTL4, LOXL4, and LOX in hypoxic MDA‐MB‐231 cells were significantly down‐regulated by DATS. DATS attenuated the metastatic potential of MDA‐MB‐231 cells in hypoxia‐induced embryonic zebrafish, xenograft, and orthotopic tumors. Endothelial cell‐cancer cell adhesion, wound healing, transwell, and tube formation assays showed that DATS dose‐dependently inhibited the migration and angiogenesis of MDA‐MB‐231 cells in vitro. The expressions of L1CAM, VEGF‐A, and EMT‐related proteins (Slug, Snail, MMP‐2) were inhibited by DATS. DATS dose‐dependently inhibited HIF‐1α transcriptional activity and hypoxia‐induced hematogenous metastasis of MDA‐MB‐231 cells. It reduced the protein expression of HIF‐1α, which did not involve inhibition of HIF‐1α mRNA expression or ubiquitin proteasome degradation. Efficient inhibition of HIF‐1α expression was required for DATS to resist breast cancer.