[Brainlife] Newsletter, Vol.4 No.15

top

BRAINLIFE NEWSLETTER

Volume 4, Number 15 - 29 March 2005	Volume 4 Archive

1: Br J Cancer. 2005 Mar 22; [Epub ahead of print]

Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma.

Arrieta O, Guevara P, Escobar E, Garcia-Navarrete R, Pineda B, Sotelo J.

1Neuroimmunology Unit of the National Institute of Neurology and Neurosurgery of Mexico, Insurgentes Sur 3877, 14269 Mexico City, Mexico.

Angiotensin II (Ang II) is a main effector peptide in the renin-angiotensin system and participates in the regulation of vascular tone. It also has a role in the expression of growth factors that induce neovascularisation which is closely associated to the growth of malignant gliomas. We have shown that the selective blockage of the AT(1) receptor of angiotensin inhibites tumour growth, cell proliferation and angiogenesis of C6 rat glioma. The aim of this study was to study the effects of the blockage of AT(1) receptor on the synthesis of growth factors, and in the genesis of apoptosis in cultured C6 glioma cells and in rats with C6 glioma. Administration of losartan at doses of 40 or 80 mg kg(-1) to rats with C6 glioma significantly decreased tumoral volume and production of platelet-derived growth factor, vascular endothelial growth factor and basic fibroblast growth factor. It also induced apoptosis in a dose-dependent manner. Administration of Ang II increased cell proliferation of cultured C6 cells which decreased by the administration of losartan. Our results suggest that the selective blockage of AT(1) diminishes tumoral growth through inhibition of growth factors and promotion of apoptosis.British Journal of Cancer advance online publication, 22 March 2005; doi:10.1038/sj.bjc.6602483 www.bjcancer.com.

PMID: 15785746 [PubMed - as supplied by publisher]

2: Br J Cancer. 2005 Feb 28;92(4):747-50.: Detection of human cytomegalovirus genome and gene products in central nervous system tumours.

Sabatier J, Uro-Coste E, Pommepuy I, Labrousse F, Allart S, Tremoulet M, Delisle MB, Brousset P.

Department of Neurosurgery, Purpan Hospital, Place Baylak, 31059 Toulouse Cedex, France.

Human cytomegalovirus (HCMV) genome and related proteins have been reported in a great proportion of malignant gliomas. However, these results are unexpected since HCMV is not known as an oncogenic virus. By immunohistochemistry (with an anti-IE1 monoclonal antibody) and in situ hybridisation (with biotinylated DNA probes) on tissue microarrays and frozen sections, we investigated a French series of central nervous system (CNS) tumours, including 97 glioblastomas. In 10 cases of glioblastoma, rare astrocyte-like cells, admixed with tumour cells, stained positively for HCMV and in one case a doubtful staining of rare cells was noticed. This may indicate a reactivation of the virus under local immunosuppression but none of the cases of CNS tumours (n=132) contained HCMV genomes and/or proteins in a significant proportion of tumour cells. Our results strongly suggest that HCMV is unlikely to be implicated in the development of human malignant gliomas, at least in French cases.

PMID: 15700045 [PubMed - indexed for MEDLINE]

3: Cancer Res. 2005 Mar 15;65(6):2353-63.: Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation.

Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, Sundaresan T, Pastorino S, Park JK, Mikolaenko I, Maric D, Eberhart CG, Fine HA.

Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

The Notch family of proteins plays an integral role in determining cell fates, such as proliferation, differentiation, and apoptosis. We show that Notch-1 and its ligands, Delta-like-1 and Jagged-1, are overexpressed in many glioma cell lines and primary human gliomas. Immunohistochemistry of a primary human glioma tissue array shows the presence in the nucleus of the Notch-1 intracellular domain, indicating Notch-1 activation in situ. Down-regulation of Notch-1, Delta-like-1, or Jagged-1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines. In addition, pretreatment of glioma cells with Notch-1 or Delta-like-1 small interfering RNA significantly prolongs survival in a murine orthotopic brain tumor model. These results show, for the first time, the dependence of cancer cells on a single Notch ligand; they also suggest a potential Notch juxtacrine/autocrine loop in gliomas. Notch-1 and its ligands may present novel therapeutic targets in the treatment of glioma.

PMID: 15781650 [PubMed - in process]

4: Cancer Res. 2005 Mar 15;65(6):2065-9.: Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis.

Uhrbom L, Kastemar M, Johansson FK, Westermark B, Holland EC.

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden. lene.uhrbom@genpat.uu.se

Homozygous deletion of the INK4a-ARF locus is one of the most frequent mutations found in human glioblastoma. We have previously shown that combined Ink4a-Arf loss can increase tumor incidence in both glial progenitor cells and astrocytes during mouse gliomagenesis. Here we have investigated the separate contribution of loss of each of the tumor suppressor genes in glial progenitor cells and astrocytes in Akt + Kras-induced gliomagenesis. We show that Arf is the major tumor suppressor gene in both cell types. Arf loss generated glioblastomas from both nestin-expressing glial progenitor cells and glial fibrillary acidic protein-expressing astrocytes, with a significantly higher incidence in astrocytes. Ink4a loss, on the other hand, could only significantly contribute to gliomagenesis from glial progenitor cells and the induced tumors were of lower malignancy than those seen in Arf-deficient mice. Thus, Ink4a and Arf have independent and differential tumor suppressor functions in vivo in the glial cell compartment.

PMID: 15781613 [PubMed - in process]

5: Clin Cancer Res. 2005 Mar 15;11(6):2258-64.: YKL-40 Is a Differential Diagnostic Marker for Histologic Subtypes of High-Grade Gliomas.

Nutt CL, Betensky RA, Brower MA, Batchelor TT, Louis DN, Stemmer-Rachamimov AO.

Molecular Neuro-Oncology Laboratory and Molecular Pathology Unit, Departments of Pathology, Cancer Center, and Neurosurgical Service.

Purpose and EXPERIMENTAL DESIGN: In modern neuro-oncology, no variable affects therapeutic decisions and prognostic estimation more than tumor classification. We showed recently that class prediction models, based on gene expression profiles, classify diagnostically challenging malignant gliomas in a manner that better correlates with clinical outcome than standard pathology. In the present study, we used immunohistochemistry to investigate YKL-40 protein expression in independent sets of glioblastomas and anaplastic oligodendrogliomas to determine whether this single marker can aid classification of these high-grade gliomas.Results and CONCLUSIONS: Glioblastomas show strikingly more YKL-40 expression than anaplastic oligodendrogliomas. Only 2 of 37 glioblastomas showed completely negative YKL-40 staining in both tumor cells and extracellular matrix, whereas 18 of 29 anaplastic oligodendrogliomas were completely negative in non-microgemistocytic tumor cells and extracellular matrix. Tumor cell staining intensity was also markedly different: 84% of glioblastomas showed strong staining intensities of 2+ or 3+ whereas 76% of anaplastic oligodendrogliomas either did not stain or stained at only 1+. YKL-40 staining provided a better class distinction of glioblastoma versus anaplastic oligodendroglioma than glial fibrillary acidic protein, the current standard immunohistochemical marker used to distinguish diagnostically challenging gliomas. Moreover, a combination of YKL-40 and glial fibrillary acidic protein immunohistochemistry afforded even greater diagnostic accuracy in anaplastic oligodendrogliomas.

PMID: 15788675 [PubMed - in process]

6: Clin Cancer Res. 2005 Mar 15;11(6):2141-8.: Morphology of tumor cell nuclei is significantly related with survival time of patients with glioblastomas.

Nafe R, Franz K, Schlote W, Schneider B.

Departments of Neuroradiology, Neurosurgery, and Neuropathology (Edinger Institute), Clinics of Johann Wolfgang Goethe University, Frankfurt, Germany; and Department of Biometrics, Medical School Hannover, Hannover, Germany.

PURPOSE: To investigate whether histomorphology of tumor cell nuclei has a significant and independent relation to survival time of patients with glioblastomas.EXPERIMENTAL DESIGN: Seventy-two tumors from 72 patients were investigated by means of digital image analysis. Proliferating and nonproliferating nuclei were separately measured and parameters of nuclear size, shape, texture, and spatial relationships (topometric parameters) were detected. Survival analysis was done regarding morphometric data together with the patients' age, the amount of resection (total or subtotal), and the classification of the tumor as a "primary" (de novo) or "secondary" glioblastoma.RESULTS: The overall relation of all morphometric data to the time of survival was highly significant (Cox analysis, P < 0.0001). Apart from the extent of surgical resection, parameters of nuclear shape and topometric variables, such as the distance between two nuclei lying nearest to each other, showed an independent and significant relation to survival time. The patients' age had also a significant but comparably slight relation to survival time.CONCLUSIONS: The morphology of tumor cell nuclei, as represented by morphometric data, shows a significant relation to survival time of patients with glioblastomas. This relation is statistically independent from the amount of surgical resection, from the patients' age and from the classification of the glioblastoma as being primary or secondary. The results support the view that histomorphometry of tumor cell nuclei is a valuable prognostic marker for patients with glioblastomas. We believe that such a marker ought to be incorporated into the formation of individual therapeutic decisions.

PMID: 15788659 [PubMed - in process]

7: Int J Cancer. 2005 Apr 10;114(3):380-6.: Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid.

Camphausen K, Cerna D, Scott T, Sproull M, Burgan WE, Cerra MA, Fine H, Tofilon PJ.

Radiation Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA. camphauk@mail.nih.gov

Valproic acid (VA) is a well-tolerated drug used to treat seizure disorders and has recently been shown to inhibit histone deacetylase (HDAC). Because HDAC modulates chromatin structure and gene expression, parameters considered to influence radioresponse, we investigated the effects of VA on the radiosensitivity of human brain tumor cells grown in vitro and in vivo. The human brain tumor cell lines SF539 and U251 were used in our study. Histone hyperacetylation served as an indicator of HDAC inhibition. The effects of VA on tumor cell radiosensitivity in vitro were assessed using a clonogenic survival assay and gammaH2AX expression was determined as a measure of radiation-induced DNA double strand breaks. The effect of VA on the in vivo radioresponse of brain tumor cells was evaluated according to tumor growth delay analysis carried out on U251 xenografts. Irradiation at the time of maximum VA-induced histone hyperacetylation resulted in significant increases in the radiosensitivity of both SF539 and U251 cells. The radiosensitization was accompanied by a prolonged expression of gammaH2AX. VA administration to mice resulted in a clearly detectable level of histone hyperacetylation in U251 xenografts. Irradiation of U251 tumors in mice treated with VA resulted in an increase in radiation-induced tumor growth delay. Valproic acid enhanced the radiosensitivity of both SF539 and U251 cell lines in vitro and U251 xenografts in vivo, which correlated with the induction of histone hyperacetylation. Moreover, the VA-mediated increase in radiation-induced cell killing seemed to involve the inhibition of DNA DSB repair. (c) 2004 Wiley-Liss, Inc.

PMID: 15578701 [PubMed - indexed for MEDLINE]

8: Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):795-808.

Integration of surgery with fractionated stereotactic radiotherapy for treatment of nonfunctioning pituitary macroadenomas.

Paek SH, Downes MB, Bednarz G, Keane WM, Werner-Wasik M, Curran WJ Jr, Andrews DW.

Department of Neurosurgery, Seoul National University, Seoul, South Korea.

OBJECTIVE: To evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) after surgery in the management of residual or recurrent nonfunctioning pituitary adenomas with respect to tumor control and the development of complications. METHODS AND MATERIALS: The clinical records of patients with nonfunctioning pituitary adenomas who underwent FSRT were retrospectively analyzed. For newly diagnosed tumors, transsphenoidal surgery was performed, and, if residual tumor was identified at 3 months, FSRT was performed. If significant tumor volume persisted, transcranial surgery was performed before FSRT. We originally initiated FSRT with 2-Gy fractions to 46 Gy. We escalated the dose to 50.4 Gy thereafter. As a final modification, we dropped the daily dose to 1.8-Gy fractions delivered within 6 weeks. High-dose conformality and homogeneity was achieved with arc beam shaping and differential beam weighting. The radiographic, endocrinologic, and visual outcomes after FSRT were evaluated. RESULTS: The 68 patients included 36 males and 32 females with an age range of 15-81 years. The median follow-up was 30 months (range, 2-82 months), and the median tumor volume was 6.2 cm(3). Of the 68 patients, 20 were treated to 46 Gy and 48 to 50-52.2 Gy. Most were treated to 50.4 Gy. Eleven patients had recurrent tumors, 54 had residual tumors, and no surgery was performed in 3 patients before FSRT. We noted no radiation-induced acute or late toxicities, except for radiation-induced optic neuropathy in 2 patients. At latest follow-up, the tumor had decreased in size in 26 patients and remained stable in 41 of the 42 remaining patients. Of the 68 patients, 4 (6%) developed hypopituitarism at 6, 11, 12, and 17 months after FSRT. Reviewing available serial Humphrey visual fields, visual fields were objectively improved in 28 patients, and remained stable in 24 patients, and worsened in 2 patients. CONCLUSION: The findings of this analysis support the use of surgery followed by FSRT as a safe, effective, and integrated treatment for nonfunctioning pituitary adenomas. Additional follow-up is needed to document the long-term tumor control rates, preservation rates for vision and pituitary function, and neurocognitive outcomes.

Publication Types:

Evaluation Studies
Review

PMID: 15708259 [PubMed - indexed for MEDLINE]

9: J Clin Oncol. 2005 Mar 1;23(7):1555-63.

Intrathecal mafosfamide: a preclinical pharmacology and phase I trial.

Blaney SM, Balis FM, Berg S, Arndt CA, Heideman R, Geyer JR, Packer R, Adamson PC, Jaeckle K, Klenke R, Aikin A, Murphy R, McCully C, Poplack DG.

Texas Children's Cancer Center, 6621 Fannin St, CC 1410 00, Houston, TX 77030-2399, USA. sblaney@txccc.org

PURPOSE: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. PATIENTS AND METHODS: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. RESULTS: The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. CONCLUSION: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Publication Types:

Clinical Trial
Clinical Trial, Phase I

PMID: 15735131 [PubMed - indexed for MEDLINE]

10: J Clin Oncol. 2005 Mar 1;23(7):1507-13.: Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma.

Nguyen PL, Chakravarti A, Finkelstein DM, Hochberg FH, Batchelor TT, Loeffler JS.

Massachusetts General Hospital, Department of Radiation Oncology, 100 Blossom St, Boston, MA 02114, USA.

PURPOSE: This study evaluates the efficacy and toxicity of whole-brain radiation therapy (WBRT) as salvage therapy for immunocompetent patients who failed initial high-dose methotrexate for primary CNS lymphoma (PCNSL). PATIENTS AND METHODS: The study cohort included 27 consecutive patients who failed initial high-dose methotrexate and then received salvage WBRT (median dose, 36 Gy). Actuarial survival was measured from the initiation of radiotherapy. RESULTS: Ten patients (37%) achieved a complete radiographic response (CR), and 10 patients (37%) a partial response to WBRT, for a 74% overall radiographic response rate. At the time of maximal response, Karnofsky performance status improved in 12 (44%) of 27 patients and at least stabilized in 67%. Median estimated survival from initiation of WBRT was 10.9 months (range, 0.3 to 63.7 months). The univariate predictor of longer survival was age less than 60 years at the time of WBRT (P = .028). Among patients who survived 4 months, achievement of a CR to WBRT by 4 months (P = .002) predicted longer survival. Late treatment-associated neurotoxicity was diagnosed in four patients (15%) and was significantly associated with total radiation doses greater than 36 Gy (P = .04). No patient treated with daily fractions less than 1.8 Gy developed late neurotoxicity. CONCLUSION: For patients with PCNSL who experience treatment failure with methotrexate, WBRT provides high response rates (74%) and a median survival of 10.9 months. Age less than 60 years and response to WBRT predict post-WBRT survival. Modest rates of late neurotoxicity (15%) were seen and were associated with a total dose greater than 36 Gy.

PMID: 15735126 [PubMed - indexed for MEDLINE]

11: J Clin Oncol. 2005 Mar 1;23(7):1491-9.: Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy.

Tekautz TM, Fuller CE, Blaney S, Fouladi M, Broniscer A, Merchant TE, Krasin M, Dalton J, Hale G, Kun LE, Wallace D, Gilbertson RJ, Gajjar A.

Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105, USA.

PURPOSE: To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH). PATIENTS AND METHODS: Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed. RESULTS: Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% +/- 11%) were significantly better than those for younger patients (EFS, 11% +/- 6%; OS, 17% +/- 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy. CONCLUSION: Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.

PMID: 15735125 [PubMed - indexed for MEDLINE]

12: J Natl Cancer Inst. 2005 Mar 16;97(6):414-6.

Search and destroy: recent research exploits adult stem cells' attraction to cancer.

Brower V.

Publication Types:

News

PMID: 15770001 [PubMed - indexed for MEDLINE]

13: Neurology. 2004 Aug 24;63(4):709.

Tumefactive neuro-Behcet disease.

Bennett DL, McCabe DJ, Stevens JM, Mifsud V, Kitchen ND, Giovannoni G.

Department of Neurology, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK. dlhbennett@talk21.com

Publication Types:

Case Reports

PMID: 15326247 [PubMed - indexed for MEDLINE]

14: Oncogene. 2005 Mar 21; [Epub ahead of print]: Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth.

Edwards LA, Thiessen B, Dragowska WH, Daynard T, Bally MB, Dedhar S.

[1] 1Department of Advanced Therapeutics, BC Cancer Agency, Vancouver, BC, Canada [2] 2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.

The tumor suppressor gene phosphatase and tensin homologue (PTEN) regulates the phosphatidylinositol-3'-kinase (PI3K) signaling pathway and has been shown to correlate with poor prognosis in high-grade astrocytomas when mutational inactivation or loss of the PTEN gene occurs. PTEN mutation leads to constitutive activation of protein kinase B (PKB)/Akt with phosphorylation at the PKB/Akt sites Thr-308 and Ser-473. Integrin-linked kinase (ILK) has been shown to regulate PKB/Akt activity with the loss of PTEN in prostate cancer. We now demonstrate that ILK activity regulates PKB/Akt activity in glioblastoma cells. The activity of ILK is constitutively elevated in a serum-independent manner in PTEN mutant cells, and transfection of wild-type PTEN under the control of an inducible promoter into mutant PTEN cells inhibits ILK activity. Transfection of ILK antisense (ILKAS) or exposure to a small-molecule ILK inhibitor suppresses the constitutive phosphorylation of PKB/Akt on Ser-473 in PTEN-mutant glioblastoma cell lines. In addition, the delivery of ILKAS to PTEN-negative glioblastoma cells resulted in apoptosis. Rag-2M mice bearing established ( approximately 100 mg) human U87MG glioblastoma tumors, treated QD x 5 for 3 consecutive weeks with ILKAS (i.p. 5 mg/kg), exhibited stable disease with </=7% increase in tumor volume over the 3-week course of treatment. In contrast, animals treated with an oligonucleotide control or saline exhibited a >100% increase in tumor volume over the same time period. Our initial results indicate that therapeutic strategies targeting ILK may be beneficial in the treatment of glioblastomas.Oncogene advance online publication, 21 March 2005; doi:10.1038/sj.onc.1208427.

PMID: 15782140 [PubMed - as supplied by publisher]

15: Oncogene. 2005 Mar 3;24(10):1718-26.: Deficiency in the gap junction protein connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner.

King TJ, Gurley KE, Prunty J, Shin JL, Kemp CJ, Lampe PD.

Cancer Prevention Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. tking@fhcrc.org

Connexin32 knockout mice (Cx32-KO) exhibit increased chemical- and radiation-induced liver and lung tumor formation with many lung tumors demonstrating decreased levels of the tumor suppressor p27KIP1. To determine if p27 deficiency alters Cx32-influenced tumorigenesis, we have generated a Cx32/p27 double-deficient mouse strain (DKO) and show here that exposure of these mice to X-ray radiation resulted in an increase or decrease in tumorigenesis depending on the tissue. Several tissues were highly sensitive to loss of p27 tumor suppressor function (intestine, adrenal, pituitary) resulting in an increased overall tumor burden in DKO mice compared to both wild-type (P<0.005) and Cx32-KO mice (P=0.066). However, additional deletion of p27 in a Cx32-KO background resulted in a statistically significant decrease in the liver tumor incidence suggesting that Cx32 and p27 pathways mechanistically interact. Immunohistochemical analysis revealed an increased percentage of Cx32-KO liver and lung tumors harboring active mitogen-activated protein kinase (Erk1, Erk2) pathways in contrast to lower percentages of activated wild-type (P<0.005) and DKO tumors (P=0.027). Increased MAPK activation in liver tumors did not correlate with Ha-ras codon-61 mutation status. This study demonstrates that tissues dependent on Cx32 tumor suppression, such as the liver and lung, exhibit altered tumorigenesis and tumor biology (MAPK pathway activation) related to p27 status.

PMID: 15608667 [PubMed - indexed for MEDLINE]

16: Oncogene. 2005 Feb 24;24(9):1525-32.: Tenascin-W is found in malignant mammary tumors, promotes alpha8 integrin-dependent motility and requires p38MAPK activity for BMP-2 and TNF-alpha induced expression in vitro.

Scherberich A, Tucker RP, Degen M, Brown-Luedi M, Andres AC, Chiquet-Ehrismann R.

Novartis Research Foundation, Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.

Tenascins represent a family of extracellular matrix glycoproteins with distinctive expression patterns. Here we have analyzed the most recently described member, tenascin-W, in breast cancer. Mammary tumors isolated from transgenic mice expressing hormone-induced oncogenes reveal tenascin-W in the stroma around lesions with a high likelihood of metastasis. The presence of tenascin-W was correlated with the expression of its putative receptor, alpha8 integrin. HC11 cells derived from normal mammary epithelium do not express alpha8 integrin and fail to cross tenascin-W-coated filters. However, 4T1 mammary carcinoma cells do express alpha8 integrin and their migration is stimulated by tenascin-W. The expression of tenascin-W is induced by BMP-2 but not by TGF-beta1, though the latter is a potent inducer of tenascin-C. The expression of tenascin-W is dependent on p38MAPK and JNK signaling pathways. Since preinflammatory cytokines also act through p38MAPK and JNK signaling pathways, the possible role of TNF-alpha in tenascin-W expression was also examined. TNF-alpha induced the expression of both tenascin-W and tenascin-C, and this induction was p38MAPK- and cyclooxygenase-dependent. Our results show that tenascin-W may be a useful diagnostic marker for breast malignancies, and that the induction of tenascin-W in the tumor stroma may contribute to the invasive behavior of tumor cells.

PMID: 15592496 [PubMed - indexed for MEDLINE]