Nerve Growth Factor Expression Correlates With Perineural Invasion and Pain in Human Pancreatic Cancer

Zhu, Zhaowen; Frieß, Helmut; diMola, Fabio F.; Zimmermann, Arthur; Graber, H.U.; Korc, Murray; Büchler, Markus W.

doi:10.1200/jco.1999.17.8.2419

Cited by 222 publications

(207 citation statements)

References 38 publications

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“…Interestingly, recent reports have shown that in some tumor types, the overexpression of both NGF and TRKA is associated with cancer-related pain syndrome (46,47). TRKA is further implicated in pain sensation from studies on subjects with congenital insensitivity to pain with anhydrosis, a rare genetic disorder in which pain perception is lacking, and for which the underlying genetic defect has recently been pinpointed to loss-of-function mutations of the TRKA gene (48).…”

Section: Discussionmentioning

confidence: 99%

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC 50 . PHA-848125-treated cells show cell cycle arrest in G 1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment. Mol Cancer Ther; 9(8); 2243-54. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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“…It does not cross-react with other neurotrophin receptors (Trk-B or Trk-C). These two antibodies have been characterized by immunocytochemistry and functional assay [17,19,47,48].…”

Section: Rna Preparation and Rt-pcr Analysis Of Ngf Gp140mentioning

confidence: 99%

NGF-withdrawal induces apoptosis in pancreatic beta cells in vitro

et al. 2001

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Beta cells originate from precursor cells in the pancreatic ducts, although the possibility of an early migration of the neuroectodermal cells to the endoderm has not been completely ruled out [1±3]. These cells share many similarities with neurons such as the expression of neuron-specific molecules, that is tyrosine hydroxylase or dopamine b-hydroxylase. They are electrically excitable like neurons and insulin release is a process resembling neurotransmitter release, involving cell depolarization and vesicle exocytosis [4]. Beta cells and neuronal cells could be sensitive to the same growth and differentiation factors since specific transcriptional activators (Islets1, Pax-6 and Beta2) are expressed in beta cells and neurons, whereas the transcriptional repressor factor NRSF/ Diabetologia (2001) Abstract Aims/hypothesis. Using primary cultures of human pancreatic islets, purified human pancreatic beta cells and the mouse bTC6-F7 cell line, we analysed the expression of nerve growth factor, (NGF/NGF) receptors in beta cells. To investigate whether NGF could sub-serve an autocrine antiapoptotic role in beta cells, we studied the effects of NGF withdrawal using a neutralizing monoclonal anti-NGF antibody.Methods. The expression of NGF and NGF receptors (gp140 Trk-A and p75 NTR ) were analysed by RT-PCR and immunofluorescence. Pulse-chase experiments and beta cell/PC12 co-cultures were used to investigate NGF production and secretion from beta cells. Possible apoptosis induced by NGF withdrawal was monitored by phosphatidylserine translocation, nucleosomal formation, DNA laddering and FACS analysis. Involvement of transcription/translation mechanisms were investigated as well as the gp140Trk-A required. Finally, signal transduction pathways typically involved in apoptotic mechanisms were analysed by western blot analysis.Results. We show that NGF and both NGF receptors, gp140Trk-A and p75 NTR are expressed in beta cells where NGF is produced and secreted in a biologically active form. NGF-withdrawal induces beta-cell transcription/translation independent apoptosis but mediated by gp140Trk-A. Analysis of signal transduction pathways revealed that NGF withdrawal inhibits the PI3-K, protein kinase B (AKT), Bad survival pathway and activates c-Jun kinase (JNK) whereas ERKs and p38 mitogen-activated protein kinase (MAPK) are not affected. Moreover, Bcl-XL, but not Bcl-2 protein expression are reduced. Conclusion/interpretaiton. We suggest that the integrity of the NGF/NGF receptor system and NGF bioavailability participate in controlling beta-cell survival in culture which represents a key issue for improving possibilities for transplantations in the treatment of diabetes. [Diabetologia (2001

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“…Although neurotrophin-mediated signaling has been extensively studied in PC12 and neuronal cells, their effects on nonneuronal cells are not fully understood. Accumulating data have demonstrated that NGF and its tyrosine kinase receptor TrkA are involved in tumor growth and the progression of non-neuronal cancers, including medullary thyroid carcinoma (McGregor et al, 1999), lung (Ricci et al, 2001), pancreatic (Zhu et al, 1999), prostatic (Weeraratna et al, 2000) and ovarian carcinomas (Davidson et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

TrkA overexpression enhances growth and metastasis of breast cancer cells

et al. 2009

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The Trk family of neurotrophin tyrosine kinase receptors is emerging as an important player in carcinogenic progression in non-neuronal tissues. Here, we show that breast tumors present high levels of TrkA and phospho-TrkA compared to normal breast tissues. To further evaluate the precise functions of TrkA overexpression in breast cancer development, we have performed a series of biological tests using breast cancer cells that stably overexpress TrkA. We show that (1) TrkA overexpression promoted cell growth, migration and invasion in vitro; (2) overexpression of TrkA per se conferred constitutive activation of its tyrosine kinase activity; (3) signal pathways including PI3K-Akt and ERK/ p38 MAP kinases were activated by TrkA overexpression and were required for the maintenance of a more aggressive cellular phenotype; and (4) TrkA overexpression enhanced tumor growth, angiogenesis and metastasis of xenografted breast cancer cells in immunodeficient mice. Moreover, recovered metastatic cells from the lungs exhibited enhanced anoikis resistance that was abolished by the pharmacological inhibitor K252a, suggesting that TrkA-promoted breast tumor metastasis could be mediated at least in part by enhancing anoikis resistance. Together, these results provide the first direct evidence that TrkA overexpression enhances the tumorigenic properties of breast cancer cells and point to TrkA as a potential target in breast cancer therapy.

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Nerve Growth Factor Expression Correlates With Perineural Invasion and Pain in Human Pancreatic Cancer

Abstract: Enhanced expression of the NGF/TrkA system may influence perineural invasion and may contribute to the pain syndrome in human pancreatic cancer.

Cited by 222 publications

References 38 publications

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

NGF-withdrawal induces apoptosis in pancreatic beta cells in vitro

TrkA overexpression enhances growth and metastasis of breast cancer cells

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