Src protein kinase pp60<sup>c‐src</sup> influences adhesion stabilization of HT‐29 colon carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow

Haier, Jörg; Gallick, Garry E.; Nicolson, Garth L.

doi:10.1046/j.1359-4117.2002.01051.x

Cited by 14 publications

(11 citation statements)

References 38 publications

(41 reference statements)

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“…Third, laminar flow promotes the adhesion of lung cancer cells [Bastida et al, 1989] and both promotes the adhesion of HT29 colon cancer cells and stabilizes already formed adhesions [Haier and Nicolson, 2000]. Indeed, one report suggests that Src may be involved in the effects of such laminar flow [Haier et al, 2002]. However, these investigators have not studied the effects of pretreatment of cancer cells with shear stress on subsequent adhesion or demonstrated the persistence of such an effect.…”

Section: Discussionmentioning

confidence: 96%

Colon cancer cell adhesion in response to Src kinase activation and actin‐cytoskeleton by non‐laminar shear stress

Thamilselvan

Patel

Zyp

et al. 2004

J of Cellular Biochemistry

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Malignant cells shed from tumors during surgical resection or spontaneous metastasis experience physical forces such as shear stress and turbulence within the peritoneal cavity during irrigation, laparoscopic air insufflation, or surgical manipulation, and within the venous or lymphatic system. Since physical forces can activate intracellular signals that modulate the biology of various cell types in vitro, we hypothesized that shear stress and turbulence might increase colon cancer cell adhesion to extracellular matrix, potentiating metastatic implantation. Primary human malignant colon cancer cells isolated from resected tumors and SW620 were subjected to shear stress and turbulence by stirring cells in suspension at 600 rpm for 10 min. Shear stress for 10 min increased subsequent SW620 colon cancer cell adhesion by 40.0 +/- 3.0% (n = 3; P < 0.001) and primary cancer cells by 41.0 +/- 3.0% to collagen I when compared to control cells. In vitro kinase assay (1.5 +/- 0.13 fold) and Western analysis (1.34 +/- 0.04 fold) demonstrated a significant increase in Src kinase activity in cells exposed shear stress. Src kinase inhibitors PP1 (0.1 microM), PP2 (20 microM), and actin-cytoskeleton stabilizer phalloidin (10 microM) prevented the shear stress stimulated cell adhesion to collagen I. Furthermore, PP2 inhibited basal (50.0 +/- 2.8%) and prevented shear stress induced src activation but phalloidin pretreatment did not. These results raise the possibility that shear stress and turbulence may stimulate the adhesion of malignant cells shed from colon cancers by a mechanism that requires both actin-cytoskeletal reorganization an independent physical force activation of Src kinase. Blocking this pathway might reduce tumor metastasis during surgical resection.

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Section: Discussionmentioning

confidence: 96%

Colon cancer cell adhesion in response to Src kinase activation and actin‐cytoskeleton by non‐laminar shear stress

Thamilselvan

Patel

Zyp

et al. 2004

J of Cellular Biochemistry

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“…There are eight members of this family: Src, Fyn, and Yes are ubiquitously expressed; Lck, Hck, Fgr, Lyn, and Blk have more tissue-restricted expression, mainly in hematopoietic cells (10). Src tyrosine kinases are known to be overexpressed in a variety of tumor types, such as human colon adenocarcinoma (11,12), breast cancer (13,14), and pancreatic carcinoma (15). Src family members are involved in numerous signaling pathways involved in proliferation, migration, tumor adhesion, and angiogenesis (16) and mediate signaling from many types of receptors including receptor tyrosine kinases (RTKs), integrins, and G-protein-coupled receptors (10).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Src Tyrosine Kinase as Treatment for Human Pancreatic Cancer Growing Orthotopically in Nude Mice

Yezhelyev

Koehl

Guba

et al. 2004

Clinical Cancer Research

122

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Purpose:The Src family comprises a family of nonreceptor intracellular tyrosine kinases that mediate a variety of cellular pathways. Src kinases are overexpressed in a variety of human tumors, including cancer of the colon, breast, and pancreas, and they are an integral part of tumor cell signaling pathways associated with migration, proliferation, adhesion, and angiogenesis.Experimental Design: We investigated whether the blockade of Src kinase by daily oral administration of the novel Src tyrosine kinase inhibitor AZM475271 [kindly provided by AstraZeneca (Macclesfield, United Kingdom)], alone or in combination with intraperitoneal gemcitabine, can inhibit growth and metastasis of orthotopically implanted human pancreatic carcinoma cells in nude mice.Results: Treatment with AZM475271 alone reduced the primary pancreatic tumor volume by approximately 40%, whereas AZM475271 plus gemcitabine reduced tumor volume by 90%. Furthermore, treatment with AZM475271 and gemcitabine significantly reduced metastasis: none of eight animals who received the combination treatment had lymph node or liver metastases, compared with five of five and three of five animals, respectively, in the control group (P ‫؍‬ 0.001). Src inhibition by AZM475271 (alone or with gemcitabine) was associated with significantly reduced tumor cell proliferation, decreased tumor microvessel density, and increased apoptosis in vivo. Moreover, these effects were all significantly increased when gemcitabine was combined with AZM475271 compared with gemcitabine alone.Conclusions: Src inhibition by AZM475271, either alone or in combination with gemcitabine, demonstrated significant antitumor and antimetastatic activity in an orthotopic nude mouse model for human pancreatic cancer. The combination of AZM475271 with gemcitabine sensitized tumor cells to the cytotoxic effect of gemcitabine.

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“…SRC kinases are overexpressed in many common tumor types, including colon [2,3], lung [4], ovarian [5,6], prostate [7], and pancreatic [8] cancers. Dysregulation of SRC function has been strongly linked to the pathogenesis of human cancers [9].…”

Section: Introductionmentioning

confidence: 99%

Identification and validation of phospho-SRC, a novel and potential pharmacodynamic biomarker for dasatinib (SPRYCEL™), a multi-targeted kinase inhibitor

Luo

Barrett

Yang

et al. 2008

Cancer Chemother Pharmacol

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Purpose Dasatinib (BMS-354825) is a potent, oral multitargeted kinase inhibitor. It is an effective therapy for patients with imatinib-resistant or -intolerant Ph+ leukemias,. It has demonstrated promising preclinical anti-tumor activity, and is under clinical evaluation in solid tumors. To support the clinical development of dasatinib, we identified a pharmacodynamic biomarker to assess in vivo SRC kinase inhibition, with subsequent evaluation in cancer patients. Methods The biomarker, phosphorylated SRC (phospho-SRC), was first identified in human prostate PC-3 tumor cells and peripheral blood mononuclear cells (PBMCs) in vitro. It was further assessed in nude mice bearing PC-3 xenografts. Phospho-SRC[pY418] in tumors and PBMC were measured by western blot analysis, and were quantified by ELISA assays. Dasatinib plasma concentrations were determined using LC/MS/MS.Results In PC-3 cells, dasatinib showed dose-dependent anti-proliferative effect, which correlated with the inhibition of phospho-SRC[pY418] and of SRC kinase activity. With a single oral dose of 50 or 15 mg/kg, tumoral phospho-SRC[pY418] was maximally inhibited at 3 h, partially reversed between 7 and 17 h, and completely recovered after 24 h post dose. At 5 mg/kg, tumoral phospho-SRC[pY418] inhibition was less pronounced and recovered more rapidly to baseline level within 24h. Dasatinib (1 mg/ kg) resulted in little inhibition. In PBMCs, a similar time course and extent of phospho-SRC[pY418] inhibition was observed. Inhibition of phospho-SRC[pY418] in vivo appeared to correlate with the preclinical in vivo efficacy and PK profiles of dasatinib in mice. Conclusions Phospho-SRC[pY418] may potentially be used as a biomarker to enable assessment of target inhibition in clinical studies exploring dasatinib antitumor activity.

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Src protein kinase pp60^c‐src influences adhesion stabilization of HT‐29 colon carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow

Cited by 14 publications

References 38 publications

Colon cancer cell adhesion in response to Src kinase activation and actin‐cytoskeleton by non‐laminar shear stress

Colon cancer cell adhesion in response to Src kinase activation and actin‐cytoskeleton by non‐laminar shear stress

Inhibition of Src Tyrosine Kinase as Treatment for Human Pancreatic Cancer Growing Orthotopically in Nude Mice

Identification and validation of phospho-SRC, a novel and potential pharmacodynamic biomarker for dasatinib (SPRYCEL™), a multi-targeted kinase inhibitor

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Src protein kinase pp60c‐src influences adhesion stabilization of HT‐29 colon carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow

Cited by 14 publications

References 38 publications

Colon cancer cell adhesion in response to Src kinase activation and actin‐cytoskeleton by non‐laminar shear stress

Colon cancer cell adhesion in response to Src kinase activation and actin‐cytoskeleton by non‐laminar shear stress

Inhibition of Src Tyrosine Kinase as Treatment for Human Pancreatic Cancer Growing Orthotopically in Nude Mice

Identification and validation of phospho-SRC, a novel and potential pharmacodynamic biomarker for dasatinib (SPRYCEL™), a multi-targeted kinase inhibitor

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Src protein kinase pp60^c‐src influences adhesion stabilization of HT‐29 colon carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow