Biomedical subjects
Fran Balkwill
Publications and source records attributed to Fran Balkwill.
Involvement of both intrinsic and extrinsic pathways in IFN-gamma-induced apoptosis that are enhanced with cisplatin.
IFN-gamma has direct anti-proliferative effects on ovarian cancer cell lines and tumour cells isolated from ovarian cancer ascites. The aim of this study was to further elucidate the mechanisms involved. An IFN-gamma-mediated cell cycle blockade was detectable in synchronised cell populations. Apoptosis, which was caspase dependent, was also induced. When caspase activity was blocked, the anti-proliferative effect of IFN-gamma was only partially reduced indicating independent roles for both growth inhibition and apoptosis in its actions. We have demonstrated involvement of the intrinsic apoptotic pathway; IFN-gamma treatment resulted in mitochondrial membrane depolarisation, cytochrome c release into the cytosol and activation of caspase 9. Cytochrome c release was blocked by the presence of a general caspase inhibitor, suggesting a role for caspases upstream of the mitochondria. One candidate is caspase 8, which was also activated in cells treated with IFN-gamma. Levels of Bid, a pro-apoptotic molecule that can mediate mitochondrial membrane permeabilisation when cleaved by caspase 8, were also decreased and indicated a potential link between these two pathways in IFN-gamma-induced apoptosis. Furthermore, together with cisplatin, IFN-gamma exerted a more powerful anti-proliferative effect.
Immunology for the next generation.
Immunologists need to establish a vibrant dialogue with young people. This is not only important for the continuation and progress of biomedical research, but it can also contribute to the fight against diseases such as HIV/AIDS and can help young people to make informed decisions about lifestyle, medical treatment and ethical issues. Good communication skills are crucial to any scientific career, and the lessons learned from talking with non-scientists can also be useful when writing scientific papers and grants. This article is a personal account of one scientist's experience of communicating biomedical science to young people.
The significance of cancer cell expression of the chemokine receptor CXCR4.
Malignant cells from at least 23 different types of cancer express the chemokine receptor CXCR4 and respond to its ligand CXCL12. This receptor ligand pair appears to be involved in directed migration of cancer cells to sites of metastasis, increased survival of cancer cells in sub optimal conditions and establishment of a tumour promoting cytokine/chemokine network. Preliminary data from animal models suggest that CXCR4 may be an important therapeutic target in a range of cancers. However CXCR4 plays major roles in embryogenesis, homeostasis and inflammation. This raises questions concerning the specificity of CXCR4 antagonists in the treatment of cancer.
Cancer and the chemokine network.
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The chemokine network in cancer--much more than directing cell movement.
Cytokine and chemokine gradients are central to the directed movement of cells in both homeostatic and pathological processes. Most cancers have a complex chemokine network which can influence immune responses to the tumor, direct the extent and cellular composition of the leukocyte infiltrate and also play a role in angiogenesis. Tumor cells can also hijack the chemokine system and gain expression of certain chemokine receptors and respond to specific chemokine gradients. Chemokine receptor expression and activation on malignant cells may be central to the growth, survival and migration of cancer cells from the primary tumor. Chemokine receptors, both CC and CXC have been detected on malignant cells and the relevant ligands are sometimes expressed at the tumor site and at sites of tumor spread, suggesting a role for the chemokine family in malignant growth and metastasis.
The inflammatory cytokine network of epithelial cancer: therapeutic implications.
A network of inflammatory cytokines and chemokines is found in epithelial cancer. There is evidence that these mediators contribute not only to tumour cell growth and survival, but also to communication between the cancer cells and stromal elements. Tumour cell production of the inflammatory cytokine tumour necrosis factor alpha (TNFalpha) is one critical factor in this autocrine and paracrine network. TNFalpha may also initiate and sustain production of other cytokines and chemokines. Chemokines are key determinants of the leukocyte infiltrate in solid ovarian tumours and influence the extent and phenotype of the infiltrate in ascitic disease. Chemokines may also be involved in tumour cell spread. Thus some of the processes involved in chronic inflammation are also active in human epithelial cancers. Agents that antagonize TNFalpha or chemokines are currently being assessed in preclinical animal cancer models and in phase I clinical trials.
Chemokine biology in cancer.
Many human cancers possess a complex chemokine network that may influence the extent and phenotype of the leukocyte infiltrate, angiogenesis, tumor cell growth, survival and migration. Restricted expression of chemokine receptors on leukocytes may allow concise control of cell movement and retention at the tumor site. Restricted and specific expression of chemokine receptors on tumor cells may be involved in the characteristic patterns of metastasis, and may promote tumor cell growth and survival. Detailed study of chemokine and chemokine receptor antagonists in experimental cancer models is warranted. Manipulation of the tumor chemokine network could have therapeutic potential in malignant disease.
IFN-gamma induces apoptosis in ovarian cancer cells in vivo and in vitro.
PURPOSE: The purpose of this study was to compare in vitro and in vivo responses of primary human tumor cells to IFN-gamma. EXPERIMENTAL DESIGN: IFN-gamma may have therapeutic activity in patients with ovarian cancer. We showed previously that this cytokine had direct antiproliferative activity against human ovarian cancer cell lines and xenografts in nude mice. To further understand the role of IFN-gamma in ovarian cancer, we compared its action on 8 ovarian cancer cell lines with the response of 14 primary cultures of ovarian tumor cells isolated from patients with ascitic disease. A pilot clinical study was then conducted to see whether IFN-gamma would also induce apoptosis in human tumor cells in vivo. Six patients with ascites and advanced disease were given IFN-gamma by i.p. injection, and sequential samples of ascites were analyzed. RESULTS: IFN-gamma had antiproliferative activity in 8 of 8 ovarian cancer cell lines and 11 of 14 primary cultures. This activity was dose related, and cleaved poly(ADP-ribose) polymerase in protein isolates provided evidence of apoptosis. In the clinical study, there was a 3 log(10) pharmacokinetic advantage in peritoneal compared with plasma levels of IFN-gamma. In two of six patients, there was a 90% reduction in tumor cells in ascites after IFN-gamma treatment, and this was related to clinical benefit as assessed by intervals between paracentesis. In all six patients, there were increased amounts of cleaved poly(ADP-ribose) polymerase in protein extracts of ascitic cells sampled during IFN-gamma treatment. CONCLUSIONS: IFN-gamma induces apoptosis in vitro and in vivo in human epithelial ovarian cancer.
The role of cytokines in the epithelial cancer microenvironment.
The epithelial tumour microenvironment is a complex tissue comprising variable numbers of tumour cells, fibroblasts, endothelial cells and infiltrating leucocytes. Cytokines are key molecules controlling autocrine or paracrine communications within and between these individual cell types. Under some circumstances, endogenous cytokines may orchestrate host responses against the tumour, but there is increasing evidence that the cytokine network contributes to tumour growth, progression and host immuno-suppression. In this review we outline some of the actions of endogenous cytokines in epithelial tumours with particular emphasis on tumour necrosis factor alpha, TNF, related inflammatory cytokines and the chemokine group of chemoattractant cytokines.
Tumor necrosis factor or tumor promoting factor?
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Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites.
PURPOSE: Ascitic disease is a common occurrence in human ovarian cancer, but it is unclear how the cellular composition of ascitic fluid is determined. Because chemokines can determine host cell infiltration in solid ovarian cancer, we assessed CC chemokine protein and CC chemokine receptor expression in ovarian cancer ascites. EXPERIMENTAL DESIGN: We used reverse transcription-PCR and RNase protection assay to determine CC chemokine and chemokine receptor mRNA expression and ELISA to measure CC chemokine protein levels. Flow cytometry was used to identify cell populations and their chemokine receptor protein expression. RESULTS: mRNA for the CC chemokines CCL2, -3, -4, -5, -8, and -22 was expressed in cell isolates from ascites samples, and the corresponding proteins were detected in ascitic fluid. mRNA for CC chemokine receptors CCR1, -2a, -2b, -3, -4, -5, and -8 was detected in cells from ascites. Fluorescence-activated cell-sorting analysis showed variable numbers of macrophages and CD3(+) T lymphocytes (predominantly CD4(+)) within ovarian cancer ascites. CD14(+) macrophages within ascites consistently expressed protein for CCR1, -2, and -5. CCR1 was expressed by >60% of all T cells, but more CD4(+) than CD8(+) T cells expressed CCR2 and -5. A direct correlation was found between the CCL5 concentration and CD3(+) T-cell infiltration. CONCLUSIONS: We conclude that there is a complex chemokine/chemokine receptor network in ovarian cancer ascites. However, associations between chemokine receptor expression, chemokine levels, and cell counts were limited.