The long-term objectives of the proposed project are to determine whether and how modulation of gap junctional intercellular communication is involved in the process of carcinogenesis.
The specific aim of the project is to test the hypothesis that blocking of communication between an initiated cell and surrounding normal cells is an important determinant in clonal expansion of the initiated cell, i.e., the tumor promotion process. Changes in intercellular communication will be examined during the process of cell transformation by measuring intercellular transfer of fluorescent dye which is microinjected into individual cells. Cell cultures, mainly BALB/c 3T3 and C3H 10T1/2 cell transformation systems, will be employed during the earlier phase of the project. Experiments are designed to answer following specific questions: (i) whether phorbol ester-mediated enhancement of cell transformation is related to the block of intercellular communication by the phorbol esters; (ii) whether so-called """"""""initiated cells"""""""" in which promotion is suppressed by retinyl acetate communicate with surrounding non-transformed cells, (iii) whether transformed cells communicate with each other and/or with surrounding non-transformed cells, and (iv) whether blocked intercellular communication also occurs during the process of promotion that is not triggered by phorbol esters. Variant cell lines that are sensitive or resistant to TPA-mediated enhancement of cell transformation (Syrian hamster embryo cells) and those that have different susceptibilities to UV- and chemically-induced transformation (BALB/c 3T3 cells) will be utilized to pursue these goals. The possibility of using the block of intercellular communication to screen tumor promoting agents will be examined. We plan to study molecular and biochemical mechanisms in detail. Our approach includes studies on (i) the molecular mechanisms by which phorbol esters inhibit the communication, with special emphasis on possible involvement of protein-kinase C activity, (ii) biochemical analysis of the factors involved in cell-cell recognition that influence gap-junctional communication, and (iii) possible oncogene involvement in blocking intercellular communication. Similar approaches will be applied to an in-vivo study using a rat-liver multistage carcinogenesis model. The microinjection technique coupled to electrophysiological measurements will be used to determine intercellular communication between preneoplastic nodules and/or hepatoma and surrounding normal cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040534-02
Application #
3180632
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1985-08-01
Project End
1988-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
International Agency for Research on Cancer
Department
Type
DUNS #
279551881
City
Lyon
State
Country
France
Zip Code
69372
Tanaka, Toshiaki; Duflot-Dancer, Agnes; Tiraby, Michele et al. (2009) Bystander effect from cytosine deaminase and uracil phosphoribosyl transferase genes in vitro: a partial contribution of gap junctions. Cancer Lett 282:43-7
Dagli, Maria Lucia Zaidan; Yamasaki, Hiroshi; Krutovskikh, Vladimir et al. (2004) Delayed liver regeneration and increased susceptibility to chemical hepatocarcinogenesis in transgenic mice expressing a dominant-negative mutant of connexin32 only in the liver. Carcinogenesis 25:483-92
Loncarek, Jadranka; Yamasaki, Hiroshi; Levillain, Pierre et al. (2003) The expression of the tumor suppressor gene connexin 26 is not mediated by methylation in human esophageal cancer cells. Mol Carcinog 36:74-81
Omori, Y; Zaidan Dagli, M L; Yamakage, K et al. (2001) Involvement of gap junctions in tumor suppression: analysis of genetically-manipulated mice. Mutat Res 477:191-6
Tanaka, T; Yamasaki, H; Mesnil, M (2001) Induction of a bystander effect in HeLa cells by using a bigenic vector carrying viral thymidine kinase and connexin32 genes. Mol Carcinog 30:176-80
Yano, T; Hernandez-Blazquez, F J; Omori, Y et al. (2001) Reduction of malignant phenotype of HEPG2 cell is associated with the expression of connexin 26 but not connexin 32. Carcinogenesis 22:1593-600
Hernandez-Blazquez, F J; Joazeiro, P P; Omori, Y et al. (2001) Control of intracellular movement of connexins by E-cadherin in murine skin papilloma cells. Exp Cell Res 270:235-47
Yano, T; Yamasaki, H (2001) Regulation of cellular invasion and matrix metalloproteinase activity in HepG2 cell by connexin 26 transfection. Mol Carcinog 31:101-9
Yamakage, K; Omori, Y; Zaidan-Dagli, M L et al. (2000) Induction of skin papillomas, carcinomas, and sarcomas in mice in which the connexin 43 gene is heterologously deleted. J Invest Dermatol 114:289-94
Saito, T; Krutovskikh, V; Marion, M J et al. (2000) Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene. Int J Cancer 86:67-70

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