Sticky and smelly issues: lessons on tumour cell and leucocyte trafficking, gene and immunotherapy of cancer

Alexandroff, A.B.; McIntyre, Catherine; Porter, Joanna C.; Zeuthen, Jesper; Vile, R. G.; Taub, Dennis D.

doi:10.1038/bjc.1998.300

Cited by 13 publications

(8 citation statements)

References 25 publications

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“…1 However, until recently, little information was available regarding the relative role of direct cytotoxicity in immunity against tumor development. The development of gene-targeted mice deficient in perforin (pfp) 2 and the discovery of several members of the tumor necrosis factor (TNF) superfamily with the capacity to induce tumor cell apoptosis [3][4][5] have paved the way to determining which effector molecules are relevant in tumor immune surveillance.…”

Section: Introductionmentioning

confidence: 99%

Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis

Street

Cretney

Smyth

2001

Blood

480

288

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Perforin (pfp) and interferon-␥ (IFN-␥ IntroductionConsiderable attention has been paid to the direct antitumor activities of cytotoxic lymphocytes within innate and acquired components of the cellular immunity. 1 However, until recently, little information was available regarding the relative role of direct cytotoxicity in immunity against tumor development. The development of gene-targeted mice deficient in perforin (pfp) 2 and the discovery of several members of the tumor necrosis factor (TNF) superfamily with the capacity to induce tumor cell apoptosis [3][4][5] have paved the way to determining which effector molecules are relevant in tumor immune surveillance. Thus far, in mouse experimental tumor systems, pfp has been demonstrated to protect the host against tumor initiation, 6 primary tumor growth, 6,7 and tumor metastasis. 8 Perforin enables the entry of granzymes that play a key role in target cell DNA fragmentation, but these serine esterases are not critical for tumor cell death mediated by effector cells. 9,10 Concerning innate cytotoxicity mediated by NK cells, a role for Fas ligand (FasL) and other TNF family members in tumor immune surveillance is less obvious. Notably, in some models involving innate antitumor activity, natural killer (NK) celldepleted mice were often significantly more susceptible to tumor metastasis than pfp-deficient mice, despite the lack of activity of FasL or TNF against these tumors in vivo. 8 These observations suggested that other pfp-independent effector functions may be contributing to tumor protection.In this light, IFN-␥ is a pleiotropic cytokine that plays a central role in innate and adaptive arms of host immune defense. 11,12 IFN-␥ is secreted by NK cells and thymus-derived T cells under certain conditions of activation. 13,14 IFN-␥ acts in various ways on host and tumor cells to favor tumor regression, but the relative role that IFN-␥ plays in antitumor responses, compared with direct cytotoxicity by effector molecules such as pfp, has not been previously evaluated. Two studies have elegantly demonstrated a role for IFN-␥ in tumor immune surveillance 15,16 ; however, neither of these determined how important IFN-␥ function was compared with direct cytotoxicity mediated by innate effector cells. Herein, we have undertaken the first study to compare directly the relative role of pfp and IFN-␥ in 3 distinct models of tumor immunity. The 3 tumor models used are distinguished by different relative contributions of NK cells and NK1.1 ϩ T (NKT) cells in host protection. Regardless of the relative role of NK and NKT cells, the creation of mice doubly deficient for pfp and IFN-␥ has demonstrated that these 2 effector arms can act independently and equally effectively yet together account for all the natural antitumor immunity mediated by NK and NKT cells. Materials and methods Mice Cell culture and chromium 51 Cr release assaysThe mouse tumor cell lines and spleen cell cultures used in this study were maintained as previously described. 8,19,20 Cytotoxicity of freshly i...

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Section: Introductionmentioning

confidence: 99%

Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis

Street

Cretney

Smyth

2001

Blood

480

288

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“…11 Modified levels of cytokines and adhesion molecules have been linked to organ infiltration and disease development in HTLV pathogenesis. [12][13][14] IFN-␥ is a pleiotropic cytokine secreted by activated T cells and natural killer (NK) cells and plays a central role in innate and adaptive arms of host antiviral and antitumor immune defense. 15,16 It acts in different ways on host and tumor cells to favor tumor regression by inducing cellular antitumor immunity, inflammation, cell cycle arrest, and apoptosis and by inhibiting angiogenesis.…”

mentioning

confidence: 99%

Enhanced tumorigenesis in HTLV-1 Tax-transgenic mice deficient in interferon-gamma

Mitra-Kaushik

Harding

Hess

et al. 2004

Blood

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The oncoprotein Tax of human T-cell leukemia virus type I (HTLV-1) is the major mediator of viral pathogenesis in infected individuals. Expression of Tax under the regulation of the human granzyme B promoter in mice results in a lymphoproliferative disorder resembling adult T-cell leukemia/lymphoma (ATL). Tax expression is associated with the production of high levels interferon-gamma (IFN-gamma) in HTLV-1-infected CD4(+) cells and Tax-transgenic tumors. We examined the role of IFN-gamma in tumorigenesis, by mating Tax-transgenic mice with a gene-specific knockout for IFN-gamma. IFN-gamma(-/-) Tax(+)-transgenic mice show accelerated tumor onset (median, 4 versus 6 months), dissemination (median, 5 versus 7 months), and death (median, 7 versus 10 months), compared with IFN-gamma(+/-) or IFN-gamma(+/+) Tax(+) mice. Pathologic and immunophenotypic characteristics of tumors from all genotypes are indistinguishable, except for enhanced interleukin 2 receptor-beta (IL-2Rbeta) and suppressed intercellular adhesion molecule-1 (ICAM-1) expression on tumors from IFN-gamma(-/-) Tax(+) transgenic mice. IFN-gamma(-/-) tumors demonstrate enhanced CD31 (platelet-endothelial CAM-1 [PECAM-1]) staining compared with those from IFN-gamma(+/-) or IFN-gamma(+/+) Tax(+) mice. Angiogenesis-specific cDNA microarray analysis identified 4 mediators of angiogenic growth differentially expressed in tumors from Tax(+)IFN-gamma(-/-) mice compared with Tax(+)IFN-gamma(+/+) littermates. As confirmed by reverse transcription-polymerase chain reaction (RT-PCR), loss of IFN-gamma results in down-regulation of tumor necrosis factor-alpha (TNF-alpha) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) while up-regulating expression of vascular endothelial growth factor (VEGF) and tenascin C. These results provide insight into a possible mechanism by which IFN-gamma contributes to host resistance against HTLV-induced tumors through an angiostatic effect.

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“…The goal of this strategy is the direction of lymphocytes to the tumor and the activation of lymphocytes to elicit an antitumoral response [71]. There have been reports on tumor suppression in mice using tumor cells transfected with various cytokine genes.…”

Section: Immunotherapymentioning

confidence: 99%

Gene therapy and gastrointestinal cancer: concepts and clinical facts

Hauses¹,

Schackert²

1999

Langenbeck's Arch Surg

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Data on 22 clinical trials on malignancies of the gastrointestinal tract are available. They utilize a variety of gene-delivery methods and target cell populations, and there is considerable variety among their strategies. Gene transfer is performed by injection of naked plasmid DNA and by use of DNA-liposome complexes and viral vectors. In some cases, the gene transfer is carried out ex vivo and the patients receive genetically modified cells, whereas other approaches deliver the vector to the target cell population in vivo. The theoretical concepts of gene therapy can be divided into three groups. One approach makes use of suicide genes comprising bacterial or viral genes that convert a nontoxic prodrug into a highly cytotoxic chemotherapeutic agent at the tumor site. This approach aims at higher therapeutic specificity and fewer side effects than with the systemic delivery of cytotoxic agents. The second strategy makes an attempt to invoke the immune system to destroy malignant cells. Different strategies, such as immunization with genetically modified tumor cells or transfer of new genes to T cells, are considered to have clinical benefits. The major advantage of these immunotherapeutic approaches is the systemic effect both on the primary tumor and on metastases. The third strategy evolved from the insight that cancer is a genetic disease caused by activation of oncogenes or inactivation of tumor-suppressor genes. Compensation of genetic defects by the downregulation of activated oncogenes or the restoration of tumor-suppressor-gene functions may be able to revert the malignant phenotype of cancer cells. Of the 22 gene-therapy trials, 17 trials focus on immunotherapy. Only two trials make use of suicide genes and, in three trials, a functional copy of the p53 tumor-suppressor gene was reintroduced into malignant cells. Modalities for gene transfer and the strategies underlying gene therapy will be discussed in the context of gastrointestinal malignancies and the potential benefits for patients.

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Sticky and smelly issues: lessons on tumour cell and leucocyte trafficking, gene and immunotherapy of cancer

Cited by 13 publications

References 25 publications

Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis

Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis

Enhanced tumorigenesis in HTLV-1 Tax-transgenic mice deficient in interferon-gamma

Gene therapy and gastrointestinal cancer: concepts and clinical facts

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