Tumor biology and experimental therapeutics

Mueller‐Klieser, Wolfgang

doi:10.1016/s1040-8428(00)00082-2

Cited by 196 publications

(159 citation statements)

References 100 publications

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“…(55,56) These characteristics make the spheroids useful as an in vitro tumor model not only for radiation studies but also for fundamental research in cell biology and cancer. (61,62) In the present study, we showed that 1 µM 17AAG enhanced the radiosensitivity of SQ20B spheroids. 17AAG also reduced the level of total and phosphorylated Akt in SQ20B spheroids.…”

Section: Discussionsupporting

confidence: 64%

Heat shock protein 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis

et al. 2005

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Activation of the PI3K-Akt pathway is known to induce tumor radioresistance. In the current study, we examined the ability of 17AAG, which decreases the levels of Hsp90 client proteins including components of the PI3K-Akt pathway, to sensitize radioresistant human squamous cell carcinoma cells to Xirradiation. Human squamous cell carcinoma cell lines (SQ20B, SCC61 and SCC13) were incubated for 16 h at 37°°°°C in medium containing 17AAG. Radiation sensitivity was determined by clonogenic assays, and protein levels were examined by western blotting. Apoptosis was determined in monolayer cells by AO/EB double staining and in spheroids using the TdT-mediated dUTP nick end labeling assay. 17AAG (0.2 µ µ µ µM) enhanced the radiosensitivity more effectively in radioresistant SQ20B and SCC13 cells than in radiosensitive SCC61 cells. However, in all three cell lines, 17AAG increased radiation-induced apoptosis by reducing the expression of EGFR and ErbB-2 and inhibiting the phosphorylation of Akt. Furthermore, 17AAG (1 µ µ µ µM) sensitized SQ20B spheroids to radiation, and inhibition of Akt activation by 17AAG increased radiation-induced apoptosis in spheroids. The findings suggest that 17AAG effectively sensitizes radioresistant cells to radiation by inhibiting the PI3K-Akt pathway. Targeting the PI3K-Akt pathway with 17AAG could be a useful strategy for radiosensitization of carcinomas. (Cancer Sci 2005; 96: 911-917) R adiation therapy is commonly used for squamous cell carcinoma of the head and neck because of its minimal cosmetic effects and its ability to preserve voice in laryngeal cancer. However, treatment failure correlates with a poorer prognosis and decreased patient survival.The EGFR family contributes to resistance to radiation and chemotherapy in many human tumors, including head and neck cancer.(1-14) ErbB-2, a member of the EGFR family, is also overexpressed in 30% of breast tumors as well as in a significant number of other cancers. (15,16) Blockade of the EGFRmediated signaling pathway enhances the sensitivity of tumor cells to radiation and several chemotherapeutic agents.The PI3K-Akt pathway is a major downstream pathway initiated by activation of the EGFR family members. (17)(18)(19)(20)(21) This pathway plays an important role in cell growth and survival. (22,23) The serine/threonine kinase Akt (also known as protein kinase B) is thought to be a downstream target of PI3K. Akt activation is responsible for desensitizing cells to apoptotic stimuli. This occurs by regulation of the transcriptional activity of both Forkhead family members (24,25) and NF-κB, (26,27) and through phosphorylation and inactivation of the apoptotic machinery including Bcl-2 homolog, Bad (28,29) and caspase-9.(30) Furthermore, Akt is amplified or overexpressed in a wide variety of human tumors.(31-33) PTEN, a tumor suppressor gene, is thought to negatively regulate the PI3K-Akt pathway.(34-36) Mutations causing PTEN to be functionally inactive are frequently detected in many human cancers and enhance Akt activity.(37) Akt acti...

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Section: Discussionsupporting

confidence: 64%

Heat shock protein 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis

et al. 2005

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“…5,10,19 The cytotoxicity of increasing concentrations (0.01-1000 mg ml À1 ) of the pro-drug GCV was tested on monolayers and Sphs of transiently bgal-or HSVtk-expressing melanoma cells. As shown in Figure 3, sparse growing monolayers derived from different tumors showed very different sensitivities to the HSVtk/GCV system.…”

Section: Cultured Tumor Cells Expressed Melanoma-specific Markersmentioning

confidence: 99%

Suicide gene therapy on spontaneous canine melanoma: correlations between in vivo tumors and their derived multicell spheroids in vitro

et al. 2009

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To validate the use of multicellular spheroids to predict the efficacy of herpes simplex thymidine kinase/ganciclovir (HSVtk/GCV) suicide gene therapy in the respective in vivo tumors, we established and characterized 15 melanomaderived cell lines from surgically excised melanoma tumors. Three HSVtk-lipofected cell lines were not sensitive to GCV in any culture configuration, other five displayed similar sensitivity as monolayers or spheroids, and only one resulted more sensitive when grown as spheroids. Other six cell lines manifested a relative multicellular resistance (MCR) phenotype growing as spheroids, compared with the same cells growing as monolayers. The reverse correlation between the MCR and the monolayers survival to HSVtk/GCV suggests that one of the main causes of MCR would be the rapid cell repopulation after suicide gene treatment. The high correlation of MCR with the spheroids radial growth and with the mitotic index of the respective originary tumors supported this re-growth involvement. A remarkable finding was the high correlation in HSVtk/GCV sensitivity between in vivo tumor and the corresponding derived cell lines growing as spheroids (R 2 ¼ 0.85). This strongly encourages the implementation of spheroids as highly realistic experimental model for optimizing and predicting the in vivo response of the respective tumors to therapeutic strategies.

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“…Such primary malignant colonies undergo through a relatively simple, avascular stage of growth, with nutrient and growth factor supply by diffusion from the local microenvironment [3,47,72]. However, a further search of available quantities of critical substrates results in a subsequent aggressive phase, with the invasion of the surrounding tissue [3,10].…”

Section: Introductionmentioning

confidence: 99%

A Hybrid Model Describing Different Morphologies of Tumor Invasion Fronts

Scianna

Preziosi

2012

Math. Model. Nat. Phenom.

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Abstract. The invasive capability is fundamental in determining the malignancy of a solid tumor. Revealing biomedical strategies that are able to partially decrease cancer invasiveness is therefore an important approach in the treatment of the disease and has given rise to multiple in vitro and in silico models. We here develop a hybrid computational framework, whose aim is to characterize the effects of the different cellular and subcellular mechanisms involved in the invasion of a malignant mass. In particular, a discrete Cellular Potts Model is used to represent the population of cancer cells at the mesoscopic scale, while a continuous approach of reaction-diffusion equations is employed to describe the evolution of microscopic variables, as the nutrients and the proteins present in the microenvironment and the matrix degrading enzymes secreted by the tumor. The behavior of each cell is then determined by a balance of forces, such as homotypic (cell-cell) and heterotypic (cell-matrix) adhesions and haptotaxis, and is mediated by the internal state of the individual, i.e. its motility. The resulting composite model quantifies the influence of changes in the mechanisms involved in tumor invasion and, more interestingly, puts in evidence possible therapeutic approaches, that are potentially effective in decreasing the malignancy of the disease, such as the alteration in the adhesive properties of the cells, the inhibition in their ability to remodel and the disruption of the haptotactic movement. We also extend the simulation framework by including cell proliferation which, following experimental evidence, is regulated by the intracellular level of growth factors. Interestingly, in spite of the increment in cellular density, the depth of invasion is not significantly increased, as one could have expected.

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Tumor biology and experimental therapeutics

Cited by 196 publications

References 100 publications

Heat shock protein 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis

Heat shock protein 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis

Suicide gene therapy on spontaneous canine melanoma: correlations between in vivo tumors and their derived multicell spheroids in vitro

A Hybrid Model Describing Different Morphologies of Tumor Invasion Fronts

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