Role of intercellular communications in breast cancer multicellular tumor spheroids after chemotherapy.
Tumor heterogeneity is an important feature that is especially involved in tumor aggressiveness. Multicellular tumor spheroids (MTS) may provide some benefits in different steps for investigation of the aggregation, organization, differentiation, and network formation of tumor cells in 3D space. This model offers a unique opportunity for improvements in the capability of a current strategy to detect the effect of an appropriate anticancer agent. The aim of this study was to investigate the cellular interactions and morphological changes following chemotherapy in a 3D breast cancer spheroid model. Distribution of the gap junction protein "connexin-43" and the tight junction protein "occludin" was investigated by immunohistochemistry. Cellular interactions were examined by using transmission and scanning electron microscopies as well as light microscopy with Giemsa staining after treating cells with doxorubicin, docetaxel, and doxorubicin/docetaxel combination. Statistical analyses showed significant changes and various alterations that were observed in all groups; however, the most prominent effect was detected in the doxorubicin/docetaxel combination group. Distinct composition as a vessel-like structure and a pseudoglandular pattern of control spheroids were detected in drug-administered groups. Immunohistochemical results were consistent with the ultrastructural changes. In conclusion, doxorubicin/docetaxel combination may be more effective than the single drug usage as shown in a 3D model. The MTS model has been found to be an appropriate and reliable method for the detection of the changes in the expression of cellular junction proteins as well as other cellular proteins occurring after chemotherapy. The MTS model can be used to validate the effects of various combinations or new chemotherapeutic agents as well as documentation of possible mechanisms of new drugs.
Oktem
G
G
Department of Histology and Embryology, Ege University School of Medicine, TR-35100 Izmir, Turkey. gulperi.oktem@ege.edu.tr
Bilir
A
A
Ayla
S
S
Yavasoglu
A
A
Goksel
G
G
Saydam
G
G
Uysal
A
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D018031:Connexin 43 / Q000187:drug effects / Q000378:metabolism; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D017348:Microscopy, Electron, Scanning Transmission; D008954:Models, Biological; D062793:Occludin; D012680:Sensitivity and Specificity; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018031:Connexin 43; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin