Hepatocytes paradoxically affect intrahepatic IFN-γ production in autoimmune hepatitis due to Gal-9 expression and TLR2/4 ligand release.

Hepatocytes are the targets in autoimmune hepatitis (AIH) that results in T cell-dependent liver injury. However, hepatocytes may also affect the hepatic T cells in AIH, but the underlying mechanisms are not fully understood. Here we report that hepatocytes could secrete galectin-9 (Gal-9) to suppress the intrahepatic production of Th1 cytokine IFN-γ and restrict AIH development, but hepatocyte damage resulted in opposite effects due to release of TLR2/4 ligands that promoted the intrahepatic production of IL-1β, IL-6, and IL-12.

Chemical induced inflammation of the liver breaks tolerance and results in autoimmune hepatitis in Balb/c mice.

Autoimmune hepatitis (AIH) is a chronic liver disease mediated by immunity, and could lead to liver fibrosis and hepatocellular carcinoma. However, the mechanisms for breaking hepatic tolerance and driving AIH still remain elusive. We herein reported that the non-specific liver inflammation triggered by carbon tetrachloride (CCl) recruited high numbers of CD4+T, CD8+T and B cells, and elevated the expression of proinflammaitory cytokines in Balb/c mice, further breaking liver tolerance and inducing autoimmune response, AIH inflammation and liver fibrosis in the presence of CYP2D6 antigen mimicry.

TGF-β1 and TNF-α synergistically induce epithelial to mesenchymal transition of breast cancer cells by enhancing TAK1 activation.

TGF-β1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-β1 alone. So far, the mechanisms underlying the induction of TGF-β1-insensitive breast cancer cells remains unclear.

IL-37 suppresses the sustained hepatic IFN-γ/TNF-α production and T cell-dependent liver injury.

T cell-dependent liver injury is an important reason for the massive hepatic damage and cirrhosis. So far it is unclear whether the development of the disease could be efficiently suppressed by anti-inflammatory cytokine that modulates innate immune cells. Here we report that anti-inflammatory cytokine IL-37 could efficiently suppress the sustained hepatic expression of IFN-γ and TNF-α, two critical cytokines for inducing hepatocyte apoptosis and liver fibrosis in T cell-dependent liver injury.

TLR2/4 ligand-amplified liver inflammation promotes initiation of autoimmune hepatitis due to sustained IL-6/IL-12/IL-4/IL-25 expression.

Autoimmune hepatitis (AIH), a serious autoimmune liver disease, can be a lifelong illness, leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). So far the mechanisms for disease initiation are largely unknown. Here we report that the amplified non-AIH liver inflammation could promote the initiation of AIH due to the sustained increase of IL-6, IL-12, IL-4, and IL-25 in the liver.

C/EBPβ enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation.

Chemoresistance is a major unmet clinical obstacle in ovarian cancer treatment. Epigenetics plays a pivotal role in regulating the malignant phenotype, and has the potential in developing therapeutically valuable targets that improve the dismal outcome of this disease. Here we show that a series of transcription factors, including C/EBPβ, GCM1, and GATA1, could act as potential modulators of histone methylation in tumor cells.

IL-35 induces N2 phenotype of neutrophils to promote tumor growth.

IL-35 is an immunosuppressive cytokine and exerts regulatory effects on T cells, B cells, macrophages and dendritic cells. Neutrophils are important innate immune cells that play key roles in tumor development. The effect of IL-35 on neutrophils remains unknown.

Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation.

Circulating tumor cells (CTCs) have been studied well in the prognosis for malignant diseases as liquid biopsy, but their contribution to tumor metastasis is not clearly defined. Here we report that CTCs could promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation and neutrophil recruitment to pre-metastatic organs. Depletion of neutrophils in vivo could effectively abrogate the promoting effect of CTCs on tumor cell metastasis.

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C.

Purpose: Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis.

Experimental Design: In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC).

14,15-EET induces the infiltration and tumor-promoting function of neutrophils to trigger the growth of minimal dormant metastases.

Infiltrating neutrophils are known to promote in the development of tumor. However, it is unclear whether and how neutrophils are involved in triggering the growth of dormant metastases. Here we show that 14,15-epoxyeicosatrienoic acid (14,15-EET) can trigger the growth of dormant micrometastases by inducing neutrophilic infiltration and converting neutrophil function.

Sirtuin 6 promotes transforming growth factor-β1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence.

Sirtuin 6 (SIRT6) can function as a tumor suppressor by suppressing aerobic glycolysis and apoptosis resistance. However, the negative effect of SIRT6 on cellular senescence implies that it may also have the potential to promote tumor development. Here we report that the upregulation of SIRT6 expression was required for transforming growth factor (TGF)-β1 and H2O2/HOCl reactive oxygen species (ROS) to promote the tumorigenicity of hepatocellular carcinoma (HCC) cells.

Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells.

In tumor-bearing state, the function of neutrophils is converted from tumor-suppressing to tumor-promoting. Here we report that priming with IFN-γ and TNF-α could convert the potential of neutrophils from tumor-promoting to tumor-suppressing. The neutrophils with protumor potential have not lost their responsiveness to IFN-γ and TNF-α.

Cyclin D1b splice variant promotes αvβ3-mediated adhesion and invasive migration of breast cancer cells.

Cyclin D1b, a splice variant of the cell cycle regulator cyclin D1, holds oncogenic functions in human cancer. However, the mechanisms underlying cyclin D1b function remain poorly understood. Here we introduced wild-type cyclin D1a or cyclin D1b variant into non-metastatic MCF-7 cells.

SIX1 promotes tumor lymphangiogenesis by coordinating TGFβ signals that increase expression of VEGF-C.

Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as VEGF-C to induce lymphangiogenesis, thereby promoting lymph node metastasis. Here, we report that sine oculis homeobox homolog 1 (SIX1), expressed in tumor cells, can promote tumor lymphangiogenesis and lymph node metastasis by coordinating with TGFβ to increase the expression of VEGF-C.

Adeno-associated virus-mediated expression of recombinant CBD-HepII polypeptide of human fibronectin inhibits metastasis of breast cancer.

CH50, a recombinant CBD-HepII polypeptide of human fibronectin, was shown to suppress tumor metastasis in murine hepatocarcinoma and melanoma models. However, the effect of CH50 on human cancer cells is still not clear. Here we evaluated the efficiency of CH50 delivered by recombinant adeno-associated virus (rAAV) vector for breast cancer treatment.

TLR4 ligand/H₂O₂ enhances TGF-β1 signaling to induce metastatic potential of non-invasive breast cancer cells by activating non-Smad pathways.

TGF-β1 has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-β1 was inefficient in inducing metastatic potential of many non-invasive human tumor cells. Here we report that the enhancement of TGF-β1 signaling is required for inducing metastatic potential of non-invasive breast cancer cells.

IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation.

Neutrophils are known to have antitumor potential. However, in recent years the tumor-promoting effect of neutrophils has been well demonstrated. So far, it remains unclear what causes the conversion of neutrophil function from tumor suppressive to tumor promoting.

Delivery of chemotherapeutic drugs in tumour cell-derived microparticles.

Cellular microparticles are vesicular plasma membrane fragments with a diameter of 100-1,000 nanometres that are shed by cells in response to various physiological and artificial stimuli. Here we demonstrate that tumour cell-derived microparticles can be used as vectors to deliver chemotherapeutic drugs. We show that tumour cells incubated with chemotherapeutic drugs package these drugs into microparticles, which can be collected and used to effectively kill tumour cells in murine tumour models without typical side effects.

Targeting nuclear factor-κB suppresses the negative effect of toll-like receptor 4 signaling on antimetastasis therapy based on targeting αvβ3.

The targeting of αvβ3 is a promising therapeutic strategy for suppressing tumor metastasis. However, it is unclear whether the therapeutic efficacy could be influenced by metastasis-promoting factor(s) in vivo. Here we report that Toll-like receptor 4 (TLR4) ligand released from damaged tumor cells or bacteria had a negative effect on the therapeutic effect of a recombinant CBD-HepII polypeptide of fibronectin (CH50) that suppresses tumor metastasis by targeting αvβ3.

Extracellular HSPA1A promotes the growth of hepatocarcinoma by augmenting tumor cell proliferation and apoptosis-resistance.

Intracellular HSP70 has been implicated as a cytoprotective protein, whereas the effect of extracellular HSP70 on tumor cells has not been fully understood to date. Here we report that extracellular HSPA1A, a stress-inducible member of HSP70 family, could promote tumor growth. HSPA1A promoted the proliferation of H22 hepatocarcinoma cells through TLR2 and TLR4 signaling.

Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes αvβ3-mediated adhesion and invasive migration.

Triggering of Toll-like receptor 4 (TLR4) on tumor cells has been found to promote tumor progression by promoting tumor cell proliferation and survival. So far, however, the effect of TLR4 signaling on tumor metastasis has not been well elucidated. Here, we report that triggering of TLR4 on metastatic breast cancer cells could reciprocally regulate the expression of αvβ3 and the expressions of TPM1 and maspin, and promote αvβ3-mediated adhesion and invasive migration of the cells.

SCF and TLR4 ligand cooperate to augment the tumor-promoting potential of mast cells.

Mast cells may have either antitumor or tumor-promoting potential. Nevertheless, mast cells in tumor microenvironment have been found to promote tumor growth. So far the mechanisms underlying the modulation of mast cell function in tumor microenvironment remains to be fully elucidated.

Tumor cell-released TLR4 ligands stimulate Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells.

Gr-1(+)CD11b(+)F4/80(+) cells play important roles in tumor development and have a negative effect on tumor immunotherapy. So far, the mechanisms underlying the regulation of their immunosuppressive phenotype by classical and alternative macrophage activation stimuli are not well elucidated. In this study, we found that molecules from necrotic tumor cells (NTC-Ms) stimulated Gr-1(+)CD11b(+)F4/80(+) cells to induce apoptosis of activated T cells but not nonstimulated T cells.