Leukemia inhibitory factor, a double-edged sword with therapeutic implications in human diseases.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the interleukin-6 (IL-6) superfamily. LIF was initially discovered as a factor to induce the differentiation of myeloid leukemia cells and thus inhibit their proliferation. Subsequent studies have highlighted the multi-functions of LIF under a wide variety of physiological and pathological conditions in a highly cell-, tissue-, and context-dependent manner. Emerging evidence has demonstrated that LIF plays an essential role in the stem cell niche, where it maintains the homeostasis and regeneration of multiple somatic tissues, including intestine, neuron, and muscle. Further, LIF exerts a crucial regulatory role in immunity and functions as a protective factor against many immunopathological diseases, such as infection, inflammatory bowel disease (IBD), and graft-verse-host disease (GVHD). It is worth noting that while LIF displays a tumor-suppressive function in leukemia, recent studies have highlighted the oncogenic role of LIF in many types of solid tumors, further demonstrating the complexities and context-dependent effects of LIF. In this review, we summarize the recent insights into the roles and mechanisms of LIF in stem cell homeostasis and regeneration, immunity, and cancer, and discuss the potential therapeutic options for human diseases by modulating LIF levels and functions.

V-CARMA: A tool for the detection and modification of antigen-specific T cells.

T cells promote our body's ability to battle cancers and infectious diseases but can act pathologically in autoimmunity. The recognition of peptides presented by major histocompatibility complex (pMHC) molecules by T cell receptors (TCRs) enables T cell-mediated responses. To modify disease-relevant T cells, new tools to genetically modify T cells and decode their antigen recognition are needed. Here, we present an approach using viruses pseudotyped with peptides loaded on MHC called V-CARMA (Viral ChimAeric Receptor MHC-Antigen) to specifically target T cells expressing cognate TCRs for antigen discovery and T cell engineering. We show that lentiviruses displaying antigens on human leukocyte antigen (HLA) class I and class II molecules can robustly infect CD8+ and CD4+ T cells expressing cognate TCRs, respectively. The infection rates of the pseudotyped lentiviruses (PLVs) are correlated with the binding affinity of the TCR to its cognate antigen. Furthermore, peptide-HLA pseudotyped lentivirus V-CARMA constructs can identify target cells from a mixed T cell population, suppress PD-1 expression on CD8+ T cells via PDCD1 shRNA delivery, and induce apoptosis in autoreactive CD4+ T cells. Thus, V-CARMA is a versatile tool for TCR ligand identification and selective T cell manipulation.

The Dual Roles of Human γδ T Cells: Anti-Tumor or Tumor-Promoting.

γδ T cells are the unique T cell subgroup with their T cell receptors composed of γ chain and δ chain. Unlike αß T cells, γδ T cells are non-MHC-restricted in recognizing tumor antigens, and therefore defined as innate immune cells. Activated γδ T cells can promote the anti-tumor function of adaptive immune cells. They are considered as a bridge between adaptive immunity and innate immunity. However, several other studies have shown that γδ T cells can also promote tumor progression by inhibiting anti-tumor response. Therefore, γδ T cells may have both anti-tumor and tumor-promoting effects. In order to clarify this contradiction, in this review, we summarized the functions of the main subsets of human γδ T cells in how they exhibit their respective anti-tumor or pro-tumor effects in cancer. Then, we reviewed recent γδ T cell-based anti-tumor immunotherapy. Finally, we summarized the existing problems and prospect of this immunotherapy.

Pathogenesis of aplastic anemia.

Aplastic anemia (AA) is a rare and life-threatening bone marrow failure (BMF) that results in peripheral blood cytopenia and reduced bone marrow hematopoietic cell proliferation. The symptoms are similar to myelofibrosis, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) making diagnosis of AA complicated. The pathogenesis of AA is complex and its mechanism needs to be deciphered on an individualized basis. This review summarizes several contributions made in trying to understand AA pathogenesis in recent years which may be helpful for the development of personalized therapies for AA.

Platelet-Derived Growth Factor D Is a Prognostic Biomarker and Is Associated With Platinum Resistance in Epithelial Ovarian Cancer.

OBJECTIVE: This study aimed to investigate whether platelet-derived growth factor D (PDGF-D) is a prognostic biomarker and is associated with platinum resistance in epithelial ovarian cancer, which has not been studied by others previously. METHODS: In this study, we detected expression of PDGF-D in ovarian cancer tissues through immunohistochemistry and Western blotting. Furthermore, we analyzed the association between PDGF-D expression and clinicopathological features including prognosis in epithelial ovarian cancer. Statistical analyses were performed by using χ test, log-rank test, Cox regression test, and Kaplan-Meier method. RESULTS: High PDGF-D expression is positively correlated with International Federation of Gynecology and Obstetrics stage (P < 0.001), histologic grade (P < 0.001), lymph node metastasis (P = 0.022), and poor prognosis (P < 0.001). Platelet-derived growth factor D in platinum-resistant cases is overexpressed compared with that in platinum-sensitive cases (P < 0.001). Obstetrics stage (P = 0.029) and PDGF-D overexpression (P < 0.001) are independently correlated with platinum resistance. CONCLUSIONS: Our study indicates that PDGF-D overexpression is an independent predictor of platinum-based chemotherapy resistance and that it may also be a potential biomarker for targeted therapy and poor prognosis.

[Innate lymphoid cells and their role in immune response regulation]. / Las células linfoides innatas y su papel en la regulación de la respuesta inmune.

Innate lymphoid cells (ILCs) are lymphocytes lacking antigen recognition receptors and become activated in response to cytokines and through microbe-associated molecular pattern (MAMP) receptors. ILCs are found mainly in mucosal tissues and participate in the immune response against infections and in chronic inflammatory conditions. ILCs are divided in ILC-1, ILC-2 and ILC-3, and these cells have analogue functions to those of immune adaptive response lymphocytes Th1, Th2 and Th17. ILC-1 express T-bet, produce IFNγ, protect against infections with intracellular microorganisms and are related to inflammatory bowel disease immunopathology. ILC-2 express GATA3, produce IL-4, IL-5, IL-13 and amphiregulin, protect against parasitic infections and are related to allergy and obesity immunopathology. ILC-3 express ROR(γt), produce IL-17 and IL-22, protect against fungal infections and contribute to tolerance to intestinal microbiota and intestinal repair. They are related to inflammatory bowel disease and psoriasis immunopathology. In general terms, ILCs maintain homeostasis and coadjuvate in the protection against infections.

Las células linfoides innatas (ILC) son linfocitos que carecen de receptores de reconocimiento de antígenos y se activan en respuesta a citocinas y a través de receptores de patrones moleculares asociados a microorganismos (MAMP). Las ILC se localizan preferentemente en las mucosas, y participan en la respuesta inmune contra infecciones y en enfermedades inflamatorias crónicas. Las ILC se dividen en ILC-1, ILC-2 e ILC-3, y estas células tienen funciones análogas a las de los linfocitos Th1, Th2 y Th17 de la respuesta inmune adaptativa. Las ILC-1 expresan T-bet, producen IFNγ, protegen contra infecciones con microorganismos intracelulares y están relacionados con la inmunopatología de la enfermedad inflamatoria intestinal. Las ILC-2 expresan GATA3, producen IL-4, IL-5, IL-13 y anfirregulina, protegen contra infecciones parasitarias y se relacionan con la inmunopatología de la alergia y la obesidad. Las ILC-3 expresan RORγt, producen IL-17 e IL-22, protegen contra infecciones con hongos y participan en la tolerancia a la microbiota intestinal y en la reparación intestinal. Se relacionan con la inmunopatología de la enfermedad inflamatoria intestinal y la psoriasis. En términos generales, las ILC mantienen la homeostasis y coadyuvan en la protección contra las infecciones.

[Effect of PDGF-C on biological characters of human dermal papilla cells in vitro].

Objective: To determine the effect of platelet-derived growth factor-C (PDGF-C) on biological characters of human hair dermal papilla cells cultured in vitro. Methods: The human dermal papilla cells(HDPCs) were isolated from human hair skin obtained from rhytidectomy procedure and then cultured in vitro. Cell counting and CCK-8 assay were used to detect the effects of PDGF-C (0,10,20,30 and 40ng/ml) on the proliferation of HDPCs at 0,1 d,2d,3d,4d,5d,6d.Under the optimal concentration, flow cytometry was used to detect cell phases. Transwell assay and cell scratch test were performed to detect cell migration. Alkaline Phosphatase Activity Assay kit was used to detect the inductive activity of HDPCs. Results: PDGF-C significantly induced the proliferation of HDPCs. PDGF-C of 30ng/mL promoted the HDPCs proliferation at a summit and increased the percentage of the cells arrested at S phase (P ＜ 0.05).PDGF-C also increased the migration populations of cultured HDPCs. The cell number in lower side of the transwell insert membrane of 30ng/ml PDGF-C treated group was (361.3 ± 24.95)while the control was (246.8 ± 7.525),showing significant difference (P ＜ 0.05).The alkaline phosphate activity of cultured HDPCs was increased comparing to the control group, the difference was significant (P ＜ 0.05). Conclusions: PDGF-C can promote the proliferation, migration and inductive activity of cultured human dermal papilla cells, which might be beneficial to promote the cultivation of human dermal papilla cells in vitro.

Vascular niches: endothelial cells as tissue- and site-specific multifunctional team players in health and disease.

The cardiovascular system is a circulatory system that transports the blood and reaches out to almost every site of the body. Endothelial cells (EC) as the innermost cell layer of blood vessels constitute a huge interface between the blood and nearly all other tissues and cells. Although blood vessels and their EC were considered as rather inert and passive conduits early in the history of vascular discoveries, progress in vascular research now suggests that EC are actively involved in a plethora of physiological or pathophysiological processes. Endothelial heterogeneity and the concept of vascular niches are in the spotlight of current research in vascular biology. Endothelial heterogeneity comprises morphologic, molecular and functional features. It allows EC to adapt to the organ- and site-specific requirements exhibited by different segments of the vascular tree. In organ-specific vascular niches, EC mutually interact with neighboring cells. EC-derived cytokines, called angiokines, acting in a paracrine (angiocrine) fashion have been shown to be decisively involved in various biological processes ranging from stem cell maintenance to organ regeneration as well as cancer progression and metastasis. In summary, EC should always be considered as teammates in the maintenance and regulation of complex multicellular network interactions in health and disease.

Gastric cancer-derived MSC-secreted PDGF-DD promotes gastric cancer progression.

PURPOSE: This study was designed to investigate the role of PDGF-DD secreted by gastric cancer-derived mesenchymal stem cells (GC-MSCs) in human gastric cancer progression. METHODS: Gastric cancer cells were indirectly co-cultured with GC-MSCs in a transwell system. The growth and migration of gastric cancer cells were evaluated by cell colony formation assay and transwell migration assay, respectively. The production of PDGF-DD in GC-MSCs was determined by using Luminex and ELISA. Neutralization of PDGFR-ß by su16f and siRNA interference of PDGF-DD in GC-MSCs was used to demonstrate the role of PDGF-DD produced by GC-MSCs in gastric cancer progression. RESULTS: GC-MSC conditioned medium promoted gastric cancer cell proliferation and migration in vitro and in vivo. Co-culture with GC-MSCs increased the phosphorylation of PDGFR-ß in SGC-7901 cells. Neutralization of PDGFR-ß by su16f blocked the promoting role of GC-MSC conditioned medium in gastric cancer cell proliferation and migration. Recombinant PDGF-DD duplicated the effects of GC-MSC conditioned medium on gastric cancer cells. Knockdown of PDGF-DD in GC-MSCs abolished its effects on gastric cancer cells in vitro and in vivo. CONCLUSIONS: PDGF-DD secreted by GC-MSCs is capable of promoting gastric cancer cell progression in vitro and in vivo. Targeting the PDGF-DD/PDGFR-ß interaction between MSCs and gastric cancer cells may represent a novel strategy for gastric cancer therapy.

Oligodendrocyte progenitor cells promote neovascularization in glioma by disrupting the blood-brain barrier.

Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)-expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain.

A critical role of the PTEN/PDGF signaling network for the regulation of radiosensitivity in adenocarcinoma of the prostate.

PURPOSE: Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model. METHODS AND MATERIALS: PTEN wild-type (PTEN+/+) and PTEN knockout (PTEN-/-) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGF D expression levels. PTEN-/- cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGF D (shPDGF D). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen. RESULTS: PTEN-/- cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGF D in these cell lines drastically diminished these phenotypes. Furthermore, PTEN-/- cells demonstrated increased clonogenic survival in vitro compared to PTEN+/+, and attenuation of PDGF D significantly reversed this radioresistant phenotype. PTEN-/- cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN-/- cells required PDGF D expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference. CONCLUSIONS: We propose that PDGF D represents a potentially promising target for PCa treatment resistance in the absence of PTEN function, and warrants further laboratory evaluation and clinical study.

Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma.

UNLABELLED: Cholangiocarcinoma (CCA) is characterized by an abundant stromal reaction. Cancer-associated fibroblasts (CAFs) are pivotal in tumor growth and invasiveness and represent a potential therapeutic target. To understand the mechanisms leading to CAF recruitment in CCA, we studied (1) expression of epithelial-mesenchymal transition (EMT) in surgical CCA specimens and CCA cells, (2) lineage tracking of an enhanced green fluorescent protein (EGFP)-expressing human male CCA cell line (EGI-1) after xenotransplantation into severe-combined-immunodeficient mice, (3) expression of platelet-derived growth factors (PDGFs) and their receptors in vivo and in vitro, (4) secretion of PDGFs by CCA cells, (5) the role of PDGF-D in fibroblast recruitment in vitro, and (6) downstream effectors of PDGF-D signaling. CCA cells expressed several EMT biomarkers, but not alpha smooth muscle actin (α-SMA). Xenotransplanted CCA masses were surrounded and infiltrated by α-SMA-expressing CAFs, which were negative for EGFP and the human Y-probe, but positive for the murine Y-probe. CCA cells were strongly immunoreactive for PDGF-A and -D, whereas CAFs expressed PDGF receptor (PDGFR)ß. PDGF-D, a PDGFRß agonist, was exclusively secreted by cultured CCA cells. Fibroblast migration was potently induced by PDGF-D and CCA conditioned medium and was significantly inhibited by PDGFRß blockade with Imatinib and by silencing PDGF-D expression in CCA cells. In fibroblasts, PDGF-D activated the Rac1 and Cdc42 Rho GTPases and c-Jun N-terminal kinase (JNK). Selective inhibition of Rho GTPases (particularly Rac1) and of JNK strongly reduced PDGF-D-induced fibroblast migration. CONCLUSION: CCA cells express several mesenchymal markers, but do not transdifferentiate into CAFs. Instead, CCA cells recruit CAFs by secreting PDGF-D, which stimulates fibroblast migration through PDGFRß and Rho GTPase and JNK activation. Targeting tumor or stroma interactions with inhibitors of the PDGF-D pathway may offer a novel therapeutic approach.

Differential effect of growth factors on invasion and proliferation of endocrine resistant breast cancer cells.

We have established several breast cancer cell lines that exhibit a permanent ER-depleted phenotype, induced by shRNA transfection of MCF-7 cells, which afford a useful model for studying acquired endocrine resistance. Previously we showed that MDA-231 as well as ER-silenced cells could invade through simulated extracellular matrix components. However, the contribution of individual serum components responsible for cell invasion was not determined. In the present study, an under-agarose gel assay was used to quantitatively assess the invasive movement of two ER-silenced cell lines (pII and YS2.5) in comparison to the parental MCF-7, the ER negative MDA-231, and normal HBL100 cells, as well as a line that was ER-shRNA transfected but failed to exhibit ER down-regulation (YS1.2). We also examined the effect of the growth factors EGF, IGF-1, TGFß, PDGFC and RANTES on pII cell invasion and proliferation. All breast cancer cell lines which had reduced ER expression exhibited a serum-dependent invasive ability related to the degree of induced ER loss. TGFß treatment inhibited pII cell proliferation and enhanced their invasive ability but at a relatively high dose. IGF-1 and EGF enhanced pII cell proliferation, with the latter playing the major role in promoting cell invasion. PDGFC did not affect either process although it is highly expressed in pII cells. Differential effects were observed on activation of Akt and ERK1/2 suggesting their involvement as intracellular mediators of EGF induced invasion, in part through the regulation of matrix metalloproteinase activity. Targeting EGF receptor tyrosine kinase activity by erlotinib resulted in significant inhibition of both pII cell proliferation and directional invasion towards EGF suggesting that this drug has potential therapeutic usefulness for preventing spread of particularly endocrine resistant breast cancer.

Generation and characterization of LIF-dependent canine induced pluripotent stem cells from adult dermal fibroblasts.

Dogs provide a more clinically relevant model of human disease than rodents, particularly with respect to hereditary diseases. Thus, the availability of canine stem cells will greatly facilitate the use of the dog in the development of stem cell-based gene therapies and regenerative medicine. In this study we describe the production of canine induced pluripotent stem cells (ciPSCs) from adult dermal fibroblasts. These cells have a morphology resembling previously described canine embryonic stem cells, a normal karyotype, and express pluripotency markers including alkaline phosphatase, Nanog, Oct4, Telomerase, SSEA1, SSEA4, TRA1-60, TRA1-81, and Rex1. Furthermore, the inactive X chromosome is reactivated indicating a ground-state pluripotency. In culture they readily form embryoid bodies, which in turn give rise to cell types from all 3 embryonic germ layers, as indicated by expression of the definitive endoderm markers Cxcr4 and α-fetoprotein, mesoderm markers Collagen IIA and Gata2, and ectoderm markers ßIII-tubulin, Enolase, and Nestin. Of particular significance is the observation that these ciPSCs are dependent only on leukemia inhibitory factor (LIF), making them similar to mouse and canine embryonic stem cells, but strikingly unlike the ciPSCs recently described in two other studies, which were dependent on both basic fibroblast growth factor and LIF in order to maintain their pluripotency. Thus, our ciPSCs closely resemble mouse ESCs derived from the inner cell mass of preimplantation embryos, while the previously described ciPSCs appear to be more representative of cells from the epiblast of mouse postimplantation embryos.

Platelet-derived growth factor-C (PDGF-C) activation by serine proteases: implications for breast cancer progression.

The PDGF (platelet-derived growth factor) family members are potent mitogens for cells of mesenchymal origin and serve as important regulators of cell migration, survival, apoptosis and transformation. Tumour-derived PDGF ligands are thought to function in both autocrine and paracrine manners, activating receptors on tumour and surrounding stromal cells. PDGF-C and -D are secreted as latent dimers, unlike PDGF-A and -B. Cleavage of the CUB domain from the PDGF-C and -D dimers is required for their biological activity. At present, little is known about the proteolytic processing of PDGF-C, the rate-limiting step in the regulation of PDGF-C activity. In the present study we show that the breast carcinoma cell line MCF7, engineered to overexpress PDGF-C, produces proteases capable of cleaving PDGF-C to its active form. Increased PDGF-C expression enhances cell proliferation, anchorage-independent cell growth and tumour cell motility by autocrine signalling. In addition, MCF7-produced PDGF-C induces fibroblast cell migration in a paracrine manner. Interestingly, PDGF-C enhances tumour cell invasion in the presence of fibroblasts, suggesting a role for tumour-derived PDGF-C in tumour-stromal interactions. In the present study, we identify tPA (tissue plasminogen activator) and matriptase as major proteases for processing of PDGF-C in MCF7 cells. In in vitro studies, we also show that uPA (urokinase-type plasminogen activator) is able to process PDGF-C. Furthermore, by site-directed mutagenesis, we identify the cleavage site for these proteases in PDGF-C. Lastly, we provide evidence suggesting a two-step proteolytic processing of PDGF-C involving creation of a hemidimer, followed by GFD-D (growth factor domain dimer) generation.

Melanoma cells control HA synthesis in peritumoral fibroblasts via PDGF-AA and PDGF-CC: impact on melanoma cell proliferation.

The microenvironment surrounding tumors has an important role in tumor progression. Fibroblasts (Fbs) of the tumor stroma receive signals from tumors and transform the extracellular matrix, thus supporting tumor growth, motility, and metastasis. The matrix component hyaluronan (HA) has a pivotal role in tumor progression. Here we analyzed the cell populations that synthesize HA in human malignant melanoma (MM) cells and studied the regulatory network between MM cells and stromal Fbs controlling HA synthesis. Tissue analysis indicated that Fbs are the main source of HA in the stroma of melanoma, whereas MM themselves synthesize only minute amounts of HA. In vitro, Fb-derived HA is mainly produced by hyaluronan synthase 2 (HAS2) and enhances proliferation of MM. Proteins secreted by MM can further increase HA synthesis in Fbs in a phosphatidylinositol 3/mitogen-activated protein-kinase-dependent manner. Melanoma cell-derived platelet-derived growth factor (PDGF)-AA and PDGF-CC were identified as major mediators that signal through PDGFR-α and thus induce HAS2-mediated HA synthesis in Fbs. In conclusion, we have identified a complex interaction of MM with its surrounding microenvironment by demonstrating that MM by the release of PDGF-AA and PDGF-CC upregulate HA synthesis in Fbs, which in turn stimulates MM proliferation in a paracrine manner.

Spatial regulation of Dia and Myosin-II by RhoGEF2 controls initiation of E-cadherin endocytosis during epithelial morphogenesis.

E-cadherin plays a pivotal role in epithelial morphogenesis. It controls the intercellular adhesion required for tissue cohesion and anchors the actomyosin-driven tension needed to change cell shape. In the early Drosophila embryo, Myosin-II (Myo-II) controls the planar polarized remodelling of cell junctions and tissue extension. The E-cadherin distribution is also planar polarized and complementary to the Myosin-II distribution. Here we show that E-cadherin polarity is controlled by the polarized regulation of clathrin- and dynamin-mediated endocytosis. Blocking E-cadherin endocytosis resulted in cell intercalation defects. We delineate a pathway that controls the initiation of E-cadherin endocytosis through the regulation of AP2 and clathrin coat recruitment by E-cadherin. This requires the concerted action of the formin Diaphanous (Dia) and Myosin-II. Their activity is controlled by the guanine exchange factor RhoGEF2, which is planar polarized and absent in non-intercalating regions. Finally, we provide evidence that Dia and Myo-II control the initiation of E-cadherin endocytosis by regulating the lateral clustering of E-cadherin.

Emerging roles of PDGF-D signaling pathway in tumor development and progression.

Platelet-derived growth factor-D (PDGF-D) can regulate many cellular processes, including cell proliferation, apoptosis, transformation, migration, invasion, angiogenesis and metastasis. Therefore PDGF-D signaling has been considered to be important in human malignancies, and thus PDGF-D signaling may represent a novel therapeutic target, and as such suggests that the development of agents that will target PDGF-D signaling is likely to have a significant therapeutic impact on human cancers. This mini-review describes the mechanisms of signal transduction associated with PDGF-D signaling to support the role of PDGF-D in the carcinogenesis. Moreover, we summarize data on several PDGF-D inhibitors especially naturally occurring "chemopreventive agent" such an indole compound, which we believe could serve as a novel agent for the prevention of tumor progression and/or treatment of human malignancies by targeted inactivation of PDGF-D signaling.

Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation.

Platelet-derived growth factor CC (PDGF-CC) is the third member of the PDGF family discovered after more than two decades of studies on the original members of the family, PDGF-AA and PDGF-BB. The biological function of PDGF-CC remains largely to be explored. We report a novel finding that PDGF-CC is a potent neuroprotective factor that acts by modulating glycogen synthase kinase 3beta (GSK3beta) activity. In several different animal models of neuronal injury, such as axotomy-induced neuronal death, neurotoxin-induced neuronal injury, 6-hydroxydopamine-induced Parkinson's dopaminergic neuronal death, and ischemia-induced stroke, PDGF-CC protein or gene delivery protected different types of neurons from apoptosis in both the retina and brain. On the other hand, loss-of-function assays using PDGF-C null mice, neutralizing antibody, or short hairpin RNA showed that PDGF-CC deficiency/inhibition exacerbated neuronal death in different neuronal tissues in vivo. Mechanistically, we revealed that the neuroprotective effect of PDGF-CC was achieved by regulating GSK3beta phosphorylation and expression. Our data demonstrate that PDGF-CC is critically required for neuronal survival and may potentially be used to treat neurodegenerative diseases. Inhibition of the PDGF-CC-PDGF receptor pathway for different clinical purposes should be conducted with caution to preserve normal neuronal functions.