Showing papers on "Growth factor receptor inhibitor published in 2013"

VEGF targets the tumour cell

Abstract: The function of vascular endothelial growth factor (VEGF) in cancer is not limited to angiogenesis and vascular permeability. VEGF-mediated signalling occurs in tumour cells, and this signalling contributes to key aspects of tumorigenesis, including the function of cancer stem cells and tumour initiation. In addition to VEGF receptor tyrosine kinases, the neuropilins are crucial for mediating the effects of VEGF on tumour cells, primarily because of their ability to regulate the function and the trafficking of growth factor receptors and integrins. This has important implications for our understanding of tumour biology and for the development of more effective therapeutic approaches.

Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells.

Abstract: Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), stem cell factor (SCF) receptor KIT, transforming growth factor-β receptors (TGF-βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3′-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up-regulation of HIFs in cancer cells may also occur in the hypoxic intratumoral regions formed within primary and secondary neoplasms as well as in leukaemic cells and metastatic prostate and breast cancer cells homing in the hypoxic endosteal niche of bone marrow. The activated HIFs may induce the expression of numerous gene products such as induced pluripotency-associated transcription factors (Oct-3/4, Nanog and Sox-2), glycolysis- and epithelial-mesenchymal transition (EMT) programme-associated molecules, including CXC chemokine receptor 4 (CXCR4), snail and twist, microRNAs and angiogenic factors such as vascular endothelial growth factor (VEGF). These gene products in turn can play critical roles for high self-renewal ability, survival, altered energy metabolism, invasion and metastases of cancer cells, angiogenic switch and treatment resistance. Consequently, the targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse.

The Role of Epidermal Growth Factor Receptor in Cancer Metastasis and Microenvironment

Abstract: Despite significant improvements in diagnosis, surgical techniques, and advancements in general patient care, the majority of deaths from cancer are caused by the metastases. There is an urgent need for an improved understanding of the cellular and molecular factors that promote cancer metastasis. The process of cancer metastasis depends on multiple interactions between cancer cells and host cells. Studies investigating the TGFα-EGFR signaling pathways that promote the growth and spread of cancer cells. Moreover, the signaling activates not only tumor cells, but also tumor-associated endothelial cells. TGFα-EGFR signaling in colon cancer cells creates a microenvironment that is conducive for metastasis, providing a rationale for efforts to inhibit EGFR signaling in TGFα-positive cancers. In this review, we describe the recent advances in our understanding of the molecular basis of cancer metastasis.

Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers

Abstract: The fibroblast growth factor receptors (FGFRs) regulate important biological processes including cell proliferation and differentiation during development and tissue repair. Over the past decades, numerous pathological conditions and developmental syndromes have emerged as a consequence of deregulation in the FGFRs signaling network. This review aims to provide an overview of FGFR family, their complex signaling pathways in tumorigenesis, and the current development and application of therapeutics targeting the FGFRs signaling for treatment of refractory human cancers.

Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1.

Abstract: The endothelium plays a pivotal role in the progression of solid tumors and is considered a highly relevant target for therapy. However, it emerges that current clinical angiogenesis inhibitors that act through inhibition of tumor-derived growth factors are prone to inducing drug resistance. Therefore, markers of tumor endothelial cells (ECs) themselves provide attractive novel therapeutic targets. In a screen for markers of tumor angiogenesis, we recently identified high-mobility group box 1 (HMGB1), known to act as proinflammatory cytokine and chromatin-binding molecule. Here we report on the role of HMGB1 in angiogenesis by showing that its overexpression is associated with an increased angiogenic potential of ECs. HMGB1 stimulates the expression of players in vascular endothelial growth factor and platelet-derived growth factor signaling, both in vitro and in vivo. Importantly, we show that HMGB1 triggers and helps to sustain this proangiogenic gene expression program in ECs, additionally characterized by increased activity of matrix metalloproteinases, integrins and nuclear factor-κB. Moreover, we found that HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of HMGB1 expression, and that of its receptors, RAGE (receptor for advanced glycation end products) and Toll-like receptor 4 (TLR4). Interference in HMGB1 expression and/or function using knockdown approaches and antibody-mediated targeting to break this vicious circle resulted in inhibited migration and sprouting of ECs. Using different in vivo models, therapeutic efficacy of HMGB1 targeting was confirmed. First, we demonstrated induction of HMGB1 expression in the chicken embryo chorioallantoic membrane (CAM) neovasculature following both photodynamic therapy and tumor challenge. We subsequently showed that anti-HMGB1 antibodies inhibited vessel density in both models, accompanied by a reduced vascular expression of angiogenic growth factor receptors. Collectively, these data identify HMGB1 as an important modulator of tumor angiogenesis and suggest the feasibility of targeting HMGB1 for multi-level cancer treatment.

MicroRNA-223 Antagonizes Angiogenesis by Targeting β1 Integrin and Preventing Growth Factor Signaling in Endothelial Cells

Abstract: Rationale: Endothelial cells in situ are largely quiescent, and their isolation and culture are associated with the switch to a proliferative phenotype. Objective: To identify antiangiogenic microRNAs expressed by native endothelial cells that are altered after isolation and culture, as well as the protein targets that regulate responses to growth factors. Methods and Results: Profiling studies revealed that miR-223 was highly expressed in freshly isolated human, murine, and porcine endothelial cells, but those levels decreased in culture. In primary cultures of endothelial cells, vascular endothelial cell growth factor and basic fibroblast growth factor further decreased miR-223 expression. The overexpression of precursor-miR-223 did not affect basal endothelial cell proliferation but abrogated vascular endothelial cell growth factor–induced and basic fibroblast growth factor–induced proliferation, as well as migration and sprouting. Inhibition of miR-223 in vivo using specific antagomirs potentiated postnatal retinal angiogenesis in wild-type mice, whereas recovery of perfusion after femoral artery ligation and endothelial sprouting from aortic rings from adult miR-223 −/y animals were enhanced. MiR-223 overexpression had no effect on the growth factor–induced activation of ERK1/2 but inhibited the vascular endothelial cell growth factor–induced and basic fibroblast growth factor–induced phosphorylation of their receptors and activation of Akt. β1 integrin was identified as a target of miR-223 and its downregulation reproduced the defects in growth factor receptor phosphorylation and Akt signaling seen after miR-223 overexpression. Reintroduction of β1 integrin into miR-223–ovexpressing cells was sufficient to rescue growth factor signaling and angiogenesis. Conclusions: These results indicate that miR-223 is an antiangiogenic microRNA that prevents endothelial cell proliferation at least partly by targeting β1 integrin.

Role of Epidermal Growth Factor Receptor Inhibitors in Epidermal Growth Factor Receptor Wild-Type Non–Small-Cell Lung Cancer

Abstract: Worldwide, the majority of patients with advanced non-small-cell lung cancer (NSCLC) do not have activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). These wild-type patients comprise a significant proportion of those treated with inhibitors of this pathway, and data from randomized trials suggest that some of these wild-type patients will derive a modest benefit from these agents. Although the detection of an activating mutation predicts for a greater likelihood of response and longer progression-free survival from an EGFR tyrosine kinase inhibitor, currently there are no biomarkers that consistently and reproducibly predict for lack of benefit in wild-type patients. Several strategies to increase the efficacy of these inhibitors in wild-type NSCLC are the subject of ongoing investigations.

Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth.

Abstract: Angiogenesis: a process of generation of new blood vessels has been proved to be necessary for sustained tumor growth and cancer progression. Inhibiting angiogenesis pathway has long been remained a significant hope for the development of novel, effective and target orientated antitumor agents arresting the tumor proliferation and metastasis. The process of neoangiogenesis as a biological process is regulated by several pro- and anti-angiogenic factors, especially vascular endothelial growth factor, fibroblast growth factor, epidermal growth factor, hypoxia inducible factor 1 and transforming growth factor. Every endothelial cell destined for vessel formation is equipped with receptors for these angiogenic peptides. Moreover, numerous other angiogenic cytokines such as platelet derived growth factor (PGDF), placenta growth factor (PGF), nerve growth factor (NGF), stem-cell factor (SCF), and interleukins-2, 4, 6 etc. These molecular players performs critical role in regulating the angiogenic switch. Couple of decade's research in molecular aspects of tumor biology has unraveled numerous structural and functional mysteries of these angiogenic peptides. In present article, a detailed update on the functional and structural peculiarities of the various angiogenic peptides is described focusing on structural opportunities made available that has potential to be used to modulate function of these angiogenic peptides in developing therapeutic agents targeting neoplastic angiogenesis. The data may be useful in the mainstream of developing novel anticancer agents targeting tumor angiogenesis. We also discuss major therapeutic agents that are currently used in angiogenesis associated therapies as well as those are subject of active research or are in clinical trials.

The VEGF signaling pathway in cancer: the road ahead.

Abstract: The vascular endothelial growth factor (VEGF) family of soluble protein growth factors consists of key mediators of angiogenesis and lymphangiogenesis in the context of tumor biology. The members of the family, VEGF-A (also known as VEGF), VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF), play important roles in vascular biology in both normal physiology and pathology. The generation of a humanized neutralizing antibody to VEGF-A (bevacizumab, also known as Avastin) and the demonstration of its benefit in numerous human cancers have confirmed the merit of an anti-angiogenesis approach to cancer treatment and have validated the VEGF-A signaling pathway as a therapeutic target. Other members of the VEGF family are now being targeted, and their relevance to human cancer and the development of resistance to anti-VEGF-A treatment are being evaluated in the clinic. Here, we discuss the potential of targeting VEGF family members in the diagnosis and treatment of cancer.

α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway

Abstract: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, recently, most of these anticancer drugs have some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed. We used α-santalol and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVECs) and Prostate tumor cells (PC-3 or LNCaP) in vitro. Tumor xenografts in nude mice were used to examine the in vivo activity of α-santalol. α-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that α-santalol inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including AKT, ERK, FAK, Src, mTOR, and pS6K in HUVEC, PC-3 and LNCaP cells. α-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. α-santalol significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model. The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Molecular docking simulation indicated that α-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. α-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

Regulation of epidermal growth factor receptor signaling by plasmid-based microRNA-7 inhibits human malignant gliomas growth and metastasis in vivo.

Abstract: MicroRNAs are endogenous, non-coding RNAs of approximately 20-22 nucleotides that regulate genes expression by binding to the 3' untranslated region (UTR) of targets mRNAs and play critical roles in cancer pathways. Malignant glioma is the most common and highly lethal central nervous system tumor for which little effective treatment is available over several decades. The purpose of this study was to explore the therapeutic potential of plasmid-based microRNA-7 (miR-7) for gliomas in vivo. Enhancing miR-7 levels in vitro could significantly induce cell apoptosis, and inhibit cell proliferation, cell migration and invasion. Western blotting analysis was performed, which indicated that miR-7 directly inhibited epidermal growth factor receptor (EGFR) and further antagonized the downstream protein kinases including ERK, Akt and Stat3. Furthermore, systemic administration of miR-7 encapsulated in cationic liposome resulted in glioma xenografts growth arrest and the metastatic nodules decrease effectively in a sequence-specific manner. In this study, miR-7 was applied in glioma treatment for the first time in vivo. Our findings suggested that the plasmid-mediated gene therapy with miR-7 appeared to be a promising candidate for the development of new antitumor and anti-metastasis treatment for human glioma.

Therapeutic potential of nitric oxide donors in the prevention and treatment of angiogenesis-inhibitor-induced hypertension

Abstract: Angiogenesis is critical to tumor growth as well as to metastases. This process is tightly regulated by pro- and anti-angiogenic growth factors and their receptors. Some of these factors are highly specific for the endothelium—e.g., vascular endothelial growth factor (VEGF). A variety of drugs that target VEGF or its receptors have been developed for the treatment of different tumor types and a number of new agents is expected to be introduced within the coming years. However, clinical experience has revealed that inhibition of VEGF induces several side effects including hypertension and renal and cardiac toxicity. Angiogenesis-inhibitor-induced hypertension represents “crux medicorum” as it is often pharmacoresistant to antihypertensive therapy. We consider two most important pathomechanisms in the development of hypertension induced by angiogenesis inhibitors. The first represents direct inhibition of NO production leading to reduced vasodilatation and the second consists in increased proliferation of vascular medial cells mediated by NO deficiency and is resulting in fixation of hypertension. Based on the results of experimental and clinical studies as well as on our clinical experience, we assume that NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects. We thoroughly documented three clinical cases of cancer patients with resistant hypertension who on receiving NO donor treatment achieved target blood pressure level and a good clinical status.

GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy.

Abstract: Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

A receptor tyrosine kinase network composed of fibroblast growth factor receptors, epidermal growth factor receptor, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, and hepatocyte growth factor receptor drives growth and survival of head and neck squamous carcinoma cell lines.

Abstract: Our laboratory has previously shown that some gefitinib-insensitive head and neck squamous cell carcinoma (HNSCC) cell lines exhibit dominant autocrine fibroblast growth factor receptor (FGFR) signaling. Herein, we deployed a whole-genome loss-of-function screen to identify genes whose knockdown potentiated the inhibitory effect of the FGFR inhibitor, AZ8010, in HNSCC cell lines. Three HNSCC cell lines expressing a genome-wide small hairpin RNA (shRNA) library were treated with AZ8010 and the abundance of shRNA sequences was assessed by deep sequencing. Under-represented shRNAs in treated cells are expected to target genes important for survival with AZ8010 treatment. Synthetic lethal hits were validated with specific inhibitors and independent shRNAs. We found that multiple alternate receptors provided protection from FGFR inhibition, including receptor tyrosine kinases (RTKs), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), and hepatocyte growth factor receptor (MET). We showed that specific knockdown of either ERBB2 or MET in combination with FGFR inhibition led to increased inhibition of growth relative to FGFR tyrosine kinase inhibitor (TKI) treatment alone. These results were confirmed using specific small molecule inhibitors of either ERBB family members or MET. Moreover, the triple combination of FGFR, MET, and ERBB family inhibitors showed the largest inhibition of growth and induction of apoptosis compared with the double combinations. These results reveal a role for alternate RTKs in maintaining progrowth and survival signaling in HNSCC cells in the setting of FGFR inhibition. Thus, improved therapies for HNSCC patients could involve rationally designed combinations of TKIs targeting FGFR, ERBB family members, and MET.

Epidermal Growth Factor Receptor as a Therapeutic Target in Glioblastoma

Abstract: Glioblastoma represents one of the most challenging problems in neurooncology Among key elements driving its behavior is the transmembrane epidermal growth factor receptor family, with the first member epidermal growth factor receptor (EGFR) centered in most studies Engagement of the extracellular domain with a ligand activates the intracellular tyrosine kinase (TK) domain of EGFR, leading to autophosphorylation and signal transduction that controls proliferation, gene transcription, and apoptosis Oncogenic missense mutations, deletions, and insertions in the EGFR gene are preferentially located in the extracellular domain in glioblastoma and cause constitutive activation of the receptor The mutant EGFR may also transactivate other cell surface molecules, such as additional members of the EGFR family and the platelet-derived growth factor receptor, which ignite signaling cascades that synergize with the EGFR-initiated cascade Because of the cell surface location and increased expression of the receptor along with its important biological function, EGFR has triggered much effort for designing targeted therapy These approaches include TK inhibition, monoclonal antibody, vaccine, and RNA-based downregulation of the receptor Treatment success requires that the drug penetrates the blood-brain barrier and has low systemic toxicity but high selectivity for the tumor While the blockade of EGFR-dependent processes resulted in experimental and clinical treatment success, cells capable of using alternative signaling ultimately escape this strategy A combination of interventions targeting tumor-specific cell surface regulators along with convergent downstream signaling pathways will likely enhance efficacy Studies on EGFR in glioblastoma have revealed much information about the complexity of gliomagenesis and also facilitated the development of strategies for targeting drivers of tumor growth and combination therapies with increasing complexity

The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer.

Abstract: Type 1 insulin-like growth factor receptor (IGF1R) signalling plays a critical role in normal cell growth, and in cancer development and progression. IGF1R and the insulin-like growth factors 1 and 2 (IGF1 and IGF2) are involved in various aspects of the malignant phenotype, suggesting that IGF1R is a potential target for cancer therapy. IGF1R is particularly important in the establishment and maintenance of the transformed phenotype, in mediating proliferation, and for the survival of tumour cells with anchorage-independent growth. IGF1R also exerts antiapoptotic activity and has a substantial influence on the control of the cell and body size. This property enables transformed cells to form macroscopic tumours and to survive the process of detachment required for metastasis. Pharmaceutical companies are investigating molecules that target IGF1R, including specific low molecular weight tyrosine kinase inhibitors and monoclonal antibodies, both of which possess various advantages and display different activity profiles. This review article focuses on the preclinical and clinical development of low molecular weight IGF1R tyrosine kinase inhibitors. It is critical to pursue a thorough molecular analysis of the metabolic activity of IGF1R to avoid possible side-effects of its inhibition.

Antiangiogenic Therapies for Advanced Hepatocellular Carcinoma

Abstract: Hepatocellular carcinoma (HCC) is a significant cause of death worldwide. HCC is a highly vascular tumor, and proangiogenic cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor may play crucial roles in this disease. Sorafenib, a multikinase inhibitor that blocks VEGF and PDGF signaling, was the first systemic therapy to demonstrate improved survival in patients with advanced HCC. Several other drugs targeting VEGF are in development. Because of the anticipation of eventual resistance to anti-VEGF therapies, drugs that also target alternative proangiogenic pathways are being investigated. Recent clinical and preclinical data along with ongoing studies are reviewed.

Induction of oxidative stress by oxidized LDL via meprinα-activated epidermal growth factor receptor in macrophages.

Abstract: Aims The aim of this study was to explore meprinα-mediated transactivation of the epidermal growth factor receptor (EGFR) and reactive oxygen species (ROS) production in macrophages. Methods and results Accelerated atherosclerotic lesions were established by administration of a high-fat diet in apolipoprotein E-deficient (apoE–/–) mice. Lentiviral overexpression of meprinα in the thoracic aortic artery during plaque formation enhanced intra-plaque macrophage induction of ROS as well as formation of atherosclerotic plaques, whereas AG1478 (specific inhibitor of the EGFR) treatment exerted the opposite effect. A meprinα inhibitor abrogated EGFR activation in mice. In cultured J774a.1 macrophages, oxidized low-density lipoprotein (OxLDL) increased ROS formation and EGFR activation through a ligand [heparin-binding epidermal growth factor-like growth factor (HB-EGF)]-dependent pathway. However, a meprinα inhibitor or specific siRNA inhibited ROS production and EGFR activation. Recombinant mouse meprinα enhanced OxLDL-stimulated production of ROS and induced HB-EGF. Inhibition of p38 mitogen-activated protein kinase by SB203580 decreased OxLDL-stimulated production of ROS. Conversely, inhibition of meprinα or PI3K-Rac1 inhibitors also decreased p38 activity in OxLDL-stimulated macrophages. In addition, inhibition of meprinα reversed OxLDL-stimulated activation of PI3K. Conclusion Meprinα promotes OxLDL-induced plaque formation and ROS release by transactivation of the EGFR, followed by activation of the PI3K/Rac1/p38 pathway.

Tyrosine kinase inhibitors (TKIs) in human and pet tumours with special reference to breast cancer: A comparative review

Abstract: Tyrosine kinase receptors (TKRs) play a key role in tumour cell proliferation and survival since they are involved in endothelial cell activation leading to tumour neoangiogenesis. In particular, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-KitR), and colony-stimulating factor 1 (CSF-1) are overexpressed or constitutively activated in human and pet malignancies. A variety of small molecule inhibitors targeting specific tyrosine kinases (known as tyrosine kinase inhibitors or TKIs) have recently been approved, or are under investigation, for the treatment of human cancer. TKI application in animal cancer is however relatively recent. This review aims to illustrate the major aspects of tyrosine kinase dysfunctions, with special regard to human and animal cancer of the mammary gland, providing an update on the background of the anti-angiogenic and anti-neoplastic properties of TKIs in human and veterinary cancer.

Opioid growth factor - opioid growth factor receptor axis inhibits proliferation of triple negative breast cancer.

Abstract: Triple negative breast cancer (TNBC) represents approximately 15% of the newly diagnosed cancers worldwide and is characterized by tissue lacking in estrogen, progesterone and human epidermal growth factor receptors. TNBC disproportionately affects younger women and women of colour, and new treatments are needed. The opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis is a determinant of cell proliferation in neoplasia, and OGF is an endogenously produced pentapeptide that inhibits cell replication by interacting with OGFr and upregulating cyclin-dependent inhibitory kinase pathways thus reducing DNA synthesis. In these studies we investigated the presence and function of the OGF-OGFr axis in two human TNBC cell lines, as well as in breast cancer cell lines containing hormonal receptors. TNBC cell lines MDA-MD-231 and BT-20, as well as human breast cancer cells SK-BR-3 and MCF-7, were examined for the presence of pentapeptide and receptors, as well as their response to OGF. Specificity of peptide and receptor was confirmed by antibody neutralization and molecular studies to knockdown classical receptor protein. The requirement for protein transcription and translation and RNA transcription were investigated. Growth of TNBC cells in the presence of OGF and standard of care chemotherapeutic agent paclitaxel was evaluated to determine both efficacy and protective effects against toxicity. OGF treatment inhibited TNBC cells in a dosage related, receptor mediated, and reversible manner. OGF was the specific endogenous opioid to inhibit cell proliferation, and this was mediated by p21 cyclin dependent inhibitory kinase pathways, and required protein and RNA synthesis. OGFr was the specific receptor involved; both peptide and receptor were detected in all four cell lines. OGF treatment inhibited growth of all cancer cell lines evaluated, and reduced cell death in cultures exposed to paclitaxel. The OGF-OGFr axis is present and functioning in TNBC cell lines, and provides a novel biological pathway as potential therapy.

Epidermal growth factor receptor tyrosine kinase inhibition up-regulates interleukin-6 in cancer cells and induces subsequent development of interstitial pneumonia.

Abstract: // Yukari Ishiguro 1,3,* , Hitoshi Ishiguro 2,3,* , and Hiroshi Miyamoto 3 1 Department of Biology and Function in the Head and Neck, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan 2 Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan 3 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York * Y. I. and H. I. contributed equally to this work. Correspondence: Yukari Ishiguro, email: // Keywords : fibrosis, EGFR-TKI, IL-6, cytokine, side-effect Received : March 15, 2013 Accepted : March 29, 2013 Published : March 31, 2013 Abstract Acute interstitial pneumonia is one of serious side effects of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment, while it often has significant clinical benefit in cancer patients. Therefore, it is necessary to clarify underlying mechanisms for the development of the adverse effects by EGFR-TKI. In the present study, we attempted to determine how EGFR-TKI treatment in cancer cells induced interstitial pneumonia. The growth of tongue cancer HSC-3 and lung cancer A549 cell lines treated with EGFR-TKI was assessed by MTT assay. Cytokines and growth factors in conditioned medium obtained from EGFR-TKI-treated cancer cells were analyzed using cytokine membrane array and ELISA. Interleukin-6 (IL-6) promoter activity was measured by luciferase assay. We found that EGFR-TKI treatment significantly decreased the cell viability yet increased expression levels of IL-6 protein and mRNA, IL-6 secretion, and IL-6 transcriptional activity in these lines. In addition, using the co-culture model and IL-6 treatment was found to increase the expression of collagen and α-actin, which were markers for fibrosis, in lung fibroblast cells. These results suggest that up-regulated IL-6 plays an important role in the development of EGFR-TKI-induced interstitial fibroblastic proliferation. Therefore, blocking of IL-6 signaling could be beneficial to cancer patients undergoing EGFR-TKI treatment for reducing the risk of its unfavorable effects.

Involvement of TGFβ1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis

Abstract: Megakaryocytes release platelets into the bloodstream by elongating proplatelets. In this study, we showed that human megakaryocytes constitutively release Transforming Growth Factor β1 and express its receptors. Importantly, Transforming Growth Factor β1 downstream signaling, through SMAD2/3 phosphorylation, was shown to be active in megakaryocytes extending proplatelets, indicating a type of autocrine stimulation on megakaryocyte development. Furthermore, inactivation of Transforming Growth Factor β1 signaling, by the receptor inhibitors SB431542 and Stemolecule ALK5 inhibitor, determined a significant decrease in proplatelet formation. Recent studies indicated a crucial role of Transforming Growth Factor β1 in the pathogenesis of primary myelofibrosis. We demonstrated that primary myelofibrosis-derived megakaryocytes expressed increased levels of bioactive Transforming Growth Factor β1; however, higher levels of released Transforming Growth Factor β1 did not lead to enhanced activation of downstream pathways. Overall, these data propose Transforming Growth Factor β1 as a new element in the autocrine regulation of proplatelet formation in vitro. Despite the increase in Transforming Growth Factor β1 this mechanism seems to be preserved in primary myelofibrosis.

EGFR/TGFα and TGFβ/CTGF Signaling in Neuroendocrine Neoplasia: Theoretical Therapeutic Targets

Abstract: Neuroendocrine neoplasms (NENs) are a heterogeneous family of malignancies whose proliferation is partially dependent on growth factors secreted by the microenvironment and the tumor itself Growth factors which were demonstrated to be important in experimental models of NENs include EGF (epidermal growth factor), TGF (transforming growth factor) α, TGFβ and CTGF (connective tissue growth factor) EGF and TGFα bind to the EGF receptor to stimulate an intact RAS/RAF/MAPK pathway, leading to the transcription of genes associated with cell proliferation, invasion and metastasis Theoretically, TGFα stimulation can be inhibited at several points of the MAPK pathway, but success is limited to NEN models and is not evident in the clinical setting TGFβ1 stimulates TGFβ receptors (TGFβRI and TGFβRII) resulting in inhibition of neuroendocrine cell growth through SMAD-mediated activation of the growth inhibitor P21WAF1/CIP1 Although some NENs are inhibited by TGFβ1, paradoxical growth is seen in experimental models of gastric and small intestinal (SI) NENs Therapeutic targeting of TGFβ1 in NENs is therefore complicated by uncertainty of the effect of TGFβ1 secretion on the direction of proliferative regulation CTGF expression is associated with more malignant clinical phenotypes in a variety of cancers, including NENs CTGF promotes growth in gastric and SI-NEN models, and is implicated as a mediator of local and distant fibrosis caused by NENs of enterochromaffin cell origin CTGF inhibitors are available, but their anti-proliferative effect has not been tested in NENs In summary, growth factors are essential for NEN proliferation, and although interventions targeting these proteins are effective in experimental models, only limited clinical efficacy has been identified

Growth differentiation factor‐15 (GDF‐15) suppresses in vitro angiogenesis through a novel interaction with connective tissue growth factor (CCN2)

Abstract: Growth differentiation factor-15 (GDF-15) and the CCN family member, connective tissue growth factor (CCN2), are associated with cardiac disease, inflammation, and cancer. The precise role and signaling mechanism for these factors in normal and diseased tissues remains elusive. Here we demonstrate an interaction between GDF-15 and CCN2 using yeast two-hybrid assays and have mapped the domain of interaction to the von Willebrand factor type C domain of CCN2. Biochemical pull down assays using secreted GDF-15 and His-tagged CCN2 produced in PC-3 prostate cancer cells confirmed a direct interaction between these proteins. To investigate the functional consequences of this interaction, in vitro angiogenesis assays were performed. We demonstrate that GDF-15 blocks CCN2-mediated tube formation in human umbilical vein endothelial (HUVEC) cells. To examine the molecular mechanism whereby GDF-15 inhibits CCN2-mediated angiogenesis, activation of αV β3 integrins and focal adhesion kinase (FAK) was examined. CCN2-mediated FAK activation was inhibited by GDF-15 and was accompanied by a decrease in αV β3 integrin clustering in HUVEC cells. These results demonstrate, for the first time, a novel signaling pathway for GDF-15 through interaction with the matricellular signaling molecule CCN2. Furthermore, antagonism of CCN2 mediated angiogenesis by GDF-15 may provide insight into the functional role of GDF-15 in disease states.

Peptide-based targeting of the platelet-derived growth factor receptor beta

Abstract: Purpose The aim of this work is to identify new ligands targeting the platelet-derived growth factor receptor beta (PDGFRβ).

Insulin-Like Growth Factor 1 Receptor Promotes the Growth and Chemoresistance of Pancreatic Cancer

Abstract: Insulin-like growth factor 1 receptor (IGF1R) plays important roles in the progression of pancreatic cancer. However, the underlying mechanism remains unclear. The purpose of this study was to investigate the effects of IGF1R knockdown on the proliferation, apoptosis and chemosensitivity of pancreatic cancer cells, and explore the possible mechanisms. Pancreatic cancer cells expressing IGF1R shRNA were established, and the cell proliferation, colony formation, and chemosensitivity to gemcitabine were examined in vitro. The activation of AKT and NF-κB was detected by Western blot analysis and luciferase assay, respectively. Xenograft mice models were established to evaluate the in vivo anti-tumor effects of IGF1R knockdown. IGF1R knockdown notably inhibited pancreatic cancer cell proliferation and colony formation, induced apoptosis, and inhibited xenograft tumor growth. Moreover, IGF1R knockdown significantly enhanced chemosensitivity to gemcitabine in pancreatic cancer cells, and this was correlated with the inhibition of PI3K/AKT and NF-κB pathways. IGF1R knockdown suppresses tumor growth and enhances chemosensitivity in pancreatic cancer via the inhibition of PI3K/AKT and NF-κB pathways, and is a promising approach to overcome the chemoresistance of pancreatic cancer.