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Growth factors are signaling molecules which bind to cell surface receptors and mediate a myriad of intracellular functions. Growth factor signaling is vital for growth and differentiation of cells under normal physiological conditions. However, aberrant signaling of these molecules via their receptors enables the cells to acquire abnormal characteristics most commonly observed in tumor cells. Tumor biology studies have revealed a central role for growth factor receptors in tumor progression. This review discusses the involvement of growth factor receptors in solid tumor formation and their value as potential anticancer drug targets.
Members of the TGFbeta superfamily of growth and differentiation factors, including the TGFbeta, BMP, activin and nodal families, play important signaling roles throughout development. This paper summarizes some of the functions of these ligands in lens development. Targeted deletion of the genes encoding one of the BMP receptors, Alk3 (BMP receptor-1A), showed that signaling through this receptor is essential for normal lens development. Lenses lacking Alk3 were smaller than normal, with thin epithelial layers. The fiber cells of Alk3 null lenses became vacuolated and degenerated within the first week after birth. Lenses lacking Alk3 function were surrounded by abnormal mesenchymal cells, suggesting that the lenses provided inappropriate signals to surrounding tissues. Lens epithelial and fiber cells contained endosomes that were associated with activated (phosphorylated) SMAD1 and SMAD2. Endosomal localization of pSMAD1 was reduced in the absence of Alk3 signaling. The presence of pSMAD2 in lens fiber cell nuclei and the observation that the activin antagonist follistatin inhibited lens cell elongation suggested that an activin-like molecule participates in lens fiber cell differentiation. Lenses deficient in type II TGFbeta receptors were clear and had fiber cells of normal morphology. This suggests that TGFbeta signaling is not essential for the normal differentiation of lens fiber cells. The targeted deletion of single or multiple receptors of the TGFbeta superfamily in the lens should further characterize the role of these signaling molecules in lens development. This approach may also provide a useful way to define the downstream pathways that are activated by these receptors during the development of the lens and other tissues.
Bone morphogenetic protein (BMP) signaling is thought to perform multiple functions in the regulation of skin appendage morphogenesis and the postnatal growth of hair follicles. However, definitive genetic evidence for these roles has been lacking. Here, we show that Cre-mediated mutation of the gene encoding BMP receptor 1A in the surface epithelium and its derivatives causes arrest of tooth morphogenesis and lack of external hair. The hair shaft and hair follicle inner root sheath (IRS) fail to differentiate, and expression of the known transcriptional regulators of follicular differentiation Msx1, Msx2, Foxn1 and Gata3 is markedly downregulated or absent in mutant follicles. Lef1 expression is maintained, but nuclear beta-catenin is absent from the epithelium of severely affected mutant follicles, indicating that activation of the WNT pathway lies downstream of BMPR1A signaling in postnatal follicles. Mutant hair follicles fail to undergo programmed regression, and instead continue to proliferate, producing follicular cysts and matricomas. These results provide definitive genetic evidence that epithelial Bmpr1a is required for completion of tooth morphogenesis, and regulates terminal differentiation and proliferation in postnatal hair follicles.
The proper formation and function of the vertebrate heart requires a multitude of specific cell and tissue interactions. These interactions drive the early specification and assembly of components of the cardiovascular system that lead to a functioning system before the attainment of the definitive cardiac and vascular structures seen in the adult. Many of these adult structures are hypothesized to require both proper molecular and physical cues to form correctly. Unlike any other organ system in the embryo, the cardiovascular system requires concurrent function and formation for the embryo to survive. An example of this complex interaction between molecular and physical cues is the formation of the valves of the heart. Both molecular cues that regulate cell transformation, migration, and extracellular matrix deposition, and physical cues emanating from the beating heart, as well as hemodynamic forces, are required for valvulogenesis. This review will focus on molecules and emerging pathways that guide early events in valvulogenesis.
We determined whether concurrent blockage of vascular endothelial growth factor (VEGF) receptor and epidermal growth factor (EGF) receptor signaling by two novel tyrosine kinase inhibitors, PTK 787 and PKI 166, respectively, can inhibit angiogenesis and, hence, the growth and metastasis of human pancreatic carcinoma in nude mice. Highly metastatic human pancreatic carcinoma L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice began receiving oral doses of PTK 787 and PKI 166 three times weekly. Some groups of mice also received i.p. injections of gemcitabine twice a week. The mice were necropsied when the control mice became moribund. Treatment with PTK 787 and PKI 166, with gemcitabine alone, or with the combination of PTK 787, PKI 166, and gemcitabine produced 69, 50, and 97% reduction in the volume of pancreatic tumors, respectively. Administration of protein tyrosine kinase inhibitors and gemcitabine also significantly decreased the incidence of lymph node and liver metastasis. The therapeutic efficacy directly correlated with a decrease in circulating proangiogenic molecules (VEGF, interleukin-8), a decrease in microvessel density, a decrease in proliferating cell nuclear antigen staining, and an increase in apoptosis of tumor cells and endothelial cells. Therapies produced by combining gemcitabine with either PKI 166 or PTK 787 were similar to those produced by combining gemcitabine with both PKI 166 and PTK 787. These results suggest that blockade of either epidermal growth factor receptor or VEGF receptor signaling combined with chemotherapy provides an effective approach to the therapy of pancreatic cancer.
Since vascular endothelial growth factor (VEGF) plays a major role in tumor angiogenesis, we determined whether blockage of VEGF receptor signaling using a novel tyrosine kinase inhibitor (PTK 787) decreases the growth and metastasis of human pancreatic carcinoma growing orthotopically in nude mice. Human pancreatic L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice were given daily oral administrations of PTK 787 alone, twice weekly i.p. injections of gemcitabine, or combination therapy. The mice were necropsied when control mice became moribund (day 35). Therapy with PTK 787 alone, gemcitabine alone, or the combination of both agents produced respectively 60%, 70%, and 81% inhibition in the volume of pancreatic cancers. The combination therapy significantly decreased the incidence of lymph node and liver metastasis, leading to a significant increase in survival. Microvessel density (MVD) was significantly decreased in tumors treated with either PTK 787 alone or PTK 787 plus gemcitabine. MVD directly correlated with tumor cell proliferation and inversely correlated with apoptosis of tumor cells and associated endothelial cells. Collectively, our results demonstrate that blockade of VEGF-R signaling may provide an additional approach to the therapy of pancreatic cancer.
Several recent papers have shown that both familial primary pulmonary hypertension (FPPH) and sporadic primary pulmonary hypertension (PPH) may have a common etiology that is associated with the inheritance and/or spontaneous development of germline mutations in the bone morphogenetic protein receptor (BMPR) type II gene. Because BMPR-II is a ubiquitously expressed receptor for a family of secreted growth factors known as the bone morphogenetic proteins (BMPs), these findings suggest that BMPs play an important role in the maintenance of normal pulmonary vascular physiology. In the present commentary we discuss the implications of these findings in the context of BMP receptor biology, and relate these data to the genetics and pulmonary pathophysiology of patients with PPH.
Alterations in endothelial cell (EC) signaling could serve as a marker of effective antiangiogenic therapy. We determined the effect of an antiangiogenic tyrosine kinase inhibitor, SU6668, on tumor EC signaling in liver metastases in mice. In vitro immunofluorescence verified that pretreatment of ECs with SU6668 before exposure to VEGF decreased in vitro phosphorylation of Erk and Akt. Using double-fluorescence immunohistochemistry, phosphorylated Erk and Akt were constitutively expressed in ECs in liver metastases in untreated mice, but SU6668 blocked activation of these signaling intermediates. Determining the activation status of the Erk and Akt signaling pathways in tumor ECs may serve as a surrogate marker for the effectiveness of antiangiogenic regimens.
Normal septation of the cardiac outflow tract requires migration of neural crest cells from the posterior rhombencephalon to the branchial arches and developing conotruncal endocardial cushions. Proper migration of these cells is mediated by a variety of molecular cues. Adhesion molecules, such as integrins, are involved in the interaction of neural crest cells with the extracellular matrix, while cadherins allow neural crest cells to interact with each other during their migration. Pax3 appears to be important for proliferation of neural crest precursors, and connexin-43-mediated gap junction communication influences the rate of migration. Endothelin and its receptors are required for normal postmigratory differentiation. Platelet-derived growth factor and retinoic acid have roles in neural crest migration and differentiation as well. Finally, the similarity between the cardiovascular malformations seen in the DiGeorge and 22q11 deletion syndromes and animal models of neural crest deficiency has led to the examination of the role of genes located near or within the DiGeorge critical region in neural crest migration.
Certain refractory neoplasms, such as glioblastoma multiforme (GBM) and melanoma, demonstrate a resistant tumor phenotype in vivo. We observed that these refractory tumor models (GBM and melanoma) contain blood vessels that are relatively resistant to radiotherapy. To determine whether the vascular endothelial growth factor receptor-2 (Flk-1/KDR) may be a therapeutic target to improve the effects of radiotherapy, we used the soluble extracellular component of Flk-1 (ExFlk), which blocks vascular endothelial growth factor binding to Flk-1 receptor expressed on the tumor endothelium. Both sFlk-1 and the Flk-1-specifc inhibitor SU5416 eliminated the resistance phenotype in GBM and melanoma microvasculature as determined by both the vascular window and Doppler blood flow methods. Human microendothelial cells and human umbilical vein endothelial cells showed minimal radiation-induced apoptosis. The Flk-1 antagonists sFlk-1 and SU5416 reverted these cell models to apoptosis-prone phenotype. Flk-1 antagonists also reverted GBM and melanoma tumor models to radiation-sensitive phenotype after treatment with 3 Gy. These findings demonstrate that the tumor microenvironment including the survival of tumor-associated endothelial cells contributes to tumor blood vessel resistance to therapy.