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At least 19 recordsLinked to original sources
PubMed1978

Growth fraction as the major determinant of multicellular tumor spheroid growth rates.

Multicellular tumor spheroids (MTS) from seven murine solid tumors have been compared in terms of their growth rate and the fraction of the cells that are in cycle. Growth rates ranged from a low of 19 micron/day through a maximum of 106 micron/day, demonstrating a far wider range of growth rates than is observed when the same tumors are grown as monolayers. Through the use of an [125I]iodouridine deoxyribose incorporation assay, it has been possible to demonstrate that cells within the MTS that are in cycle double at a slower rate than they do in monolayers and that the depth of the dividing shell ranges from less than 20 to more than 100 micron. The depth of the dividing shell or the growth fraction is highly correlated with the MTS growth rate (r = 0.97). We conclude that the major factor that determines the wide range of MTS growth rates, in spite of relatively uniform doubling times in monolayer, is the fraction of the cells that are in cycle.

Cell Cycle↗
PubMed1977

A simplified method for production and growth of multicellular tumor spheroids.

A new technique, based on the growth of tumor cells in liquid media over an agar base, has been developed for the formation and growth of multicellular tumor spheroids. All of the 11 transformed cell lines tested formed multicellular tumor spheroids, while none of the 8 normal cell types tested did so. The advantages of the present technique over older methods include its simplicity, generality, and experimental flexibility.

Agar↗
PubMed1978

In vitro analysis of the response of multicellular tumor spheroids exposed to chemotherapeutic agents in vitro or in vivo.

Multicellular tumor spheroids (MTS) have been exposed to chemotherapeutic agents in vitro (nitrogen mustard) or in vivo (cyclophosphamide) and analyzed in vitro in terms of altered growth patterns. Whether the MTS were exposed in vitro or in vivo, the major effect of the drugs was to induce a dose-dependent lag period before the normal MTS growth rate resumed. Exposure of MTS in the peritoneal cavity to i.v. injection cyclophosphamide results in patterns similar to the in vitro exposure system, except that a host anti-MTS reaction was detected. In combination, these two methods allow the study of the responses of these complex tumor forms to chemotherapy.

Animals↗
PubMed1992

[Combination chemotherapy of solid tumor--effects of hyaluronidase on doxorubicin (DXR) penetration into multicellular tumor spheroids (MTS)].

We have studied the effects of hyaluronidase (HYD) on the penetration and cell kill effect of doxorubicin (DXR) using multicellular tumor spheroids (MTS). MTS of approximately 500 microns in diameter were prepared by liquid over lay culture technique from PC-10 lung and HEp-2 laryngeal squamous carcinoma cell lines. Cells in MTS and monolayer were exposed for various durations to HYD, followed by 1 hr, rest interval, and by 1 hr. exposure to DXR. MTS and monolayer cells were then trypsinized to a single cell suspension and subjected to clonogenic assay. For PC-10 MTS, pretreatment with HYD for 24 hr. resulted in approximately 10-fold increases in DXR cell kill effects as compared to DXR alone. HEp-2 MTS were more sensitive to HYD pretreatment. Thus, 1 hr. exposure to HYD produced approximately 4-fold increases in DXR-induced cell lethality. Fluorescent microscopic study revealed that 1hr. exposure of MTS to DXR produced DXR fluorescence only 1-2 outer layer of MTS. When MTS were pretreated with HYD, there was an enhanced penetration of DXR fluorescence into the MTS core. HYD-induced enhancement of DXR penetration and its cell kill effect was dependent on the exposure time and tumor cell origin.

Carcinoma, Squamous Cell↗
PubMed1992

Antiproliferative effects of free and liposome-encapsulated retinoic acid in a squamous carcinoma model: monolayer cells and multicellular tumor spheroids.

Antiproliferative effects of free retinoic acid (RA) and liposome-encapsulated RA (RAlp) were compared in a squamous carcinoma system using both monolayer cells and multicellular tumor spheroids (MTS), an in-vivo-like model with three-dimensional histological structure. Initial studies examined the effect of lipid composition on the efficiency of RA encapsulation and on the subsequent toxicity of RAlp to red blood cells. In 5-day growth assays for monolayer cells, RA and RAlp (1 microM-0.1 nM) produced similar growth inhibition. In 6-day growth assays for MTS, RAlp was shown to have increased effectiveness. Liposomal uptake by the squamous carcinoma cells was examined by culturing monolayers and MTS with fluorescence-tagged liposomes and examining them under fluorescence microscopy between days 1 and 6. Phagocytosed liposomes were present, but their low levels suggested that other mechanisms of drug delivery such as adsorption, fusion or direct lipid transfer probably occurred for RAlp. Histological examination of MTS showed that RA and RAlp produced similar alterations. In this squamous carcinoma system, liposomes are effective in delivering retinoic acid and in producing biological effects in monolayer cells and within the three-dimensional structure of MTS.

Carcinoma, Squamous Cell↗
PubMed1978

Multicellular tumor spheroid formation by breast cancer cells isolated from different sites.

Fourteen breast cancer lines (8 human, 5 rat, and 1 mouse) have been studied in terms of their ability to form multicellular tumor spheroids (MTS) with the agar-base method. Only 8 of the lines formed MTS in contrast to a 100% efficiency in a series of 11 varied tumors reported in the initial studies with this method. We have compared the lines that do and do not form MTS in terms of a variety of characteristics (e.g., estrogen receptors, time in serial passage, growth in nude mice, etc.), and only one characteristic, the source of the original tumor cells, was predictive of MTS-forming ability. All 8 of the breast cancer lines (and the original 11 lines) that formed MTS had been obtained from solid growths (primaries or metastases), while the 6 breast cancer lines that did not form MTS were all derived from pleural effusions. Similarly, artificial selection for an ascites variant of the MTS-forming rat 13762 adenocarcinoma line produced the 13762-A line, which could no longer form MTS. These results suggest that breast cancer cells derived from pleural effusions are genetically different from the bulk of the tumor cells in solid breast cancer samples, that they are unable to grow in true solid form, and that these differences persist in spite of prolonged propagation in tissue culture.

Adaptation, Physiological↗
PubMed1992

Effects of folinic acid on 5-fluorouracil induced cell lethality with or without cisplatin against head and neck laryngeal squamous carcinoma multicellular tumor spheroids.

We evaluated the efficacy of folinic acid (Leucovorin, LV) on cell lethality induced by 5-fluorouracil (FU) alone or in combination with cisplatin (DDP) by using the HEp-2 laryngeal squamous carcinoma multicellular tumor spheroids (MTS) system. For LV, non-toxic concentration of 10(-5) M was used. For cells in the monolayer, 6 and 24 h exposure to LV increased FU-induced cell lethality approximately 7- and 2-fold, respectively, whereas LV did not influence the effect of FU for MTS. LV's lack of effect on cells in MTS may be interpreted to mean that LV cannot penetrate the MTS. For the monolayer, simultaneous exposure to 3 drugs, DDP, FU and LV, produced synergistic interaction. However, sequential exposures were marginally synergistic or antagonistic, irrespective of sequence of DDP first or last. In contrast, DDP followed by FU plus LV was most synergistic for MTS. Simultaneous exposure was also synergistic, however, FU plus LV followed by DDP was antagonistic. These results suggest that LV is unable to penetrate into the MTS core to potentiate FU activity. DDP appears to have enhanced LV penetration into the MTS core. The exploration of means to overcome limited penetration of LV appears important for successful treatment of head and neck carcinoma.

Carcinoma, Squamous Cell↗
PubMed1992

Production of stable phenotypes from 9L rat brain tumor multicellular spheroids treated with 1,3-bis(2-chloroethyl)-1-nitrosourea.

During chemotherapy and regrowth of brain tumors, tumor-cell heterogeneity, and possibly tumor progression, may change as a result of both the selective forces and mutagenic effects of treatment. We have isolated and characterized drug-response variants of multicellular rat 9L brain-tumor spheroids exposed to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Ten colonies were isolated from spheroids disaggregated immediately after treatment, and 10 colonies were isolated from treated spheroids disaggregated after 1 week in suspension culture. The sensitivity to BCNU was determined by assays of sister chromatid exchange and colony-forming efficiency in monolayer cultures of each subline after a 1-hr exposure to graded doses of BCNU. Three classes of response were found: BCNU sensitivity increased, decreased, or was comparable to that of uncloned, parent 9L cells. Resistant phenotypes were predominant (8/10) in sublines from spheroids disaggregated immediately after treatment, whereas hypersensitive phenotypes (4/8) were isolated only from spheroids disaggregated after 1 week of regrowth. Since subpopulations isolated immediately after treatment do not have the same biological characteristics as those isolated after a period of regrowth, these data suggest that tumor-cell heterogeneity may be generated by distinct processes at various times during therapy. The predominance of hypersensitive sublines obtained by the regrowth protocol may have resulted from the recovery of cells that would have died if isolated but were instead able to repair the drug-induced damage when left in contact with neighboring, possibly resistant cells. Two resistant and two hypersensitive sublines were studied further.

Animals↗
PubMed1992

Penetration of anti-melanoma immunotoxin into multicellular tumor spheroids and cell kill effects.

In order to gain a better understanding of the interaction between immunotoxins and tumor cells at the level of three-dimensional tumor mass, we evaluated the cell kill effects of monoclonal antimelanoma-antibody/ricin-A-chain immunotoxin (ITN) on melanoma cells in multicellular tumor spheroids (MTS) as well as the penetration of ITN into MTS. For Minor melanoma cells in monolayer the ITN exerted cytotoxic effects after as little as 1 h of exposure. Increasing exposure time resulted in progressive increases in cytotoxic activity. In contrast, the cell kill effects of ITN were markedly delayed and reduced when Minor cells were in MTS. The ITN cytotoxic effects on the melanoma MTS were more than 100 fold less than those in monolayer. Patterns of ITN-induced cytotoxicities for Minor and for another melanoma cell line, DND-1A, were comparable. The native ricin A was more active against PC-10 squamous lung cancer cells than Minor cells, whereas the ITN was more cytotoxic against Minor cells than PC-10 cells, thus exhibiting selectivity. An autoradiographic study revealed time-dependent penetration of radiolabeled ITN from the surface of Minor MTS into the core. Incubation for 1 h resulted in the penetration of ITN into only the two or three outer layers of the Minor MTS, and low grain counts. Prolonged exposure resulted in inhomogeneous penetration of ITN into almost the entire melanoma MTS. Penetration of ITN into PC-10 MTS was extremely poor. The reduced cytotoxicity of ITN on melanoma cells in MTS as compared to cells grown in monolayer appears to correlate with its inhomogeneous distribution in the MTS. The delayed cytotoxicity of ITN is also consistent with its slow penetration into the core of the MTS.

Antibodies, Monoclonal↗
PubMed1979

Morphological and functional characteristics of cells infiltrating and destroying tumor multicellular spheroids in vivo.

EMT6 mammary sarcoma cells were grown in vitro as multicellular spheroids to model for the heterogeneity of microenvironments and structural changes which develop in many tumors, including micrometastases. Spheroids of 700-900 micron diameter were implanted into and recovered at different times from the peritoneal cavities of sensitized or nonsensitized allogeneic and syngeneic mice. The colony forming efficiency of spheroid tumor cells recovered at 24 and 48 h from sensitized allogeneic mice was markedly decreased as compared with those from nonsensitized allogeneic or syngeneic animals. These recovered spheroids were extensively infiltrated by both lymphocytes and macrophages, which ultrastructurally had very close membrane associations with tumor cells. Host cells recovered from spheroids exhibited cytotoxic activity in an in vitro 51Cr release assay. Thus, multicellular spheroids in vivo provide a unique experimental model to study the functional capacity of host cells within a spheroical tumor. Although lacking the stroma and the vasculature of in vivo solid tumors, this model does have many similarities to in vivo tumors and is thus suitable for studying the tumor cell-host cell interactions within the tumor microenvironment. In addition, the system offers the potential for quantitative study of the effects of treatment modalities on tumor cell-host cell interactions.

Animals↗
PubMed1991

Modeling autostimulation of growth in multicellular tumor spheroids.

We report the development of a growth model that includes the positive regulatory feedback by cell-cell interactions. It is based on the model by Wheldon et al. (J Theor Biol, 38 (1973) 627) and Cox et al. (Comput Biomed Res, 13 (1980) 445) and is characterized by biologically interpretable parameters. We applied the model to growth of multicellular spheroids formed by V79 Chinese hamster fibroblasts. The new model resulted in a statistically sound fit. We compared the applicability of our model, of the model by Wheldon et al. and Cox et al. as well as of the related model by Piantadosi (Comput Biomed Res, 18 (1985) 220). We affiliated the models with each other within a nesting scheme and compared their respective fits to data by the F-test. Our model yielded a fit statistically equivalent to the fit by the model of Piantadosi. However, in distinction to other models, the estimated cellular doubling time in our model agreed better with the respective experimentally determined value.

Animals↗
PubMed1979

Density gradient centrifugation of cells separated from multicellular tumor spheroids.

Cells from a murine fibrosarcome (FSa) have been grown in vitro as multicell tumor spheroids (MTS). The growth rate of these MTS was determined. Following selected periods of growth, MTS were made into a single cell suspension and separated on linear density gradients of Renografin. While only 1 population of cells were separated from small spheriods (400 mum diameter), at least 3 subpopulations of tumor cells were separated and isolated from large spheroids (800 mum in diameter).

Animals↗
PubMed1978

Dormancy and spontaneous recurrence of human breast cancer in vitro.

Monolayer cultures of the human breast cancer cell line MDA-361 require insulin for growth and for maintenance of viability, as is evidenced by rapid and complete degeneration of the cells after the removal of insulin from the medium. Detachment from the plastic surface occurs within 24 to 48 hr, and the rare (less than 0.1%) cell that remains attached doubles every 3 to 4 weeks. Multicellular tumor spheroids, derived from this same tumor cell line, enter a dormant phase which lasts approximately 6 weeks, when insulin is removed from the medium. During this dormant period the multicellular tumor spheroids appear healthy and gradually become less dependent on and more responsive to insulin. This dormant period culminates in spontaneous regrowth in the absence of insulin after the sixth week, and this growth continues at least through 3 months. In this respect these multicellular tumor spheroids parallel the behavior of residual tumors in vivo; the residual tumor remains viable but nongrowing for a prolonged period only to resume growth following escape from the growth-limiting mechanism.

Adaptation, Physiological↗
PubMed2025

3D Cell Culture Models as a Platform for Studying Tumor Progression, Testing Treatment Responses, and Discovering Biomarkers.

In this chapter, we present a detailed protocol for establishing a three-dimensional (3D) multicellular tumor spheroids (MCTSs) model to simulate the tumor microenvironment (ME) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) for the study of hepatocellular carcinoma (HCC) and colorectal cancer (CRC) cell aggressiveness, growth, and metastasis potential. The MASLD microenvironment (MASLD-ME) is recreated by embedding hepatic stellate cells in a collagen I matrix within a Boyden chamber system. The metabolic medium mimics MASLD conditions, enriched with high glucose, fructose, insulin, and fatty acids, to simulate metabolic stresses associated with the disease.In the protocol, cancer cells are loaded in the upper compartment to analyze their migration toward the MASLD-ME, thereby facilitating studies on cancer cell invasiveness and metastatic capacity. This method offers an adaptable, reproducible model to research disease progression and investigate therapeutic interventions, contributing to preclinical research on MASLD-related liver cancer pathophysiology and potential drug responses.

Humans↗
PubMed2026

MicroRNAs and predicted targets in the switch from monolayered to spheroids of cholangiocarcinoma cells.

BACKGROUND: Extrahepatic cholangiocarcinoma (eCCA) is characterized by marked molecular heterogeneity and limited therapeutic options. MicroRNAs (miRNAs) are key post-transcriptional regulators of cancer-related pathways, but their contribution to tumor adaptation in physiologically relevant models remains poorly understood. Three-dimensional (3D) tumor spheroids better mimic in vivo conditions than conventional two-dimensional (2D) cultures. METHODS: We compared miRNA expression profiles in two eCCA cell lines (Sk-ChA-1 and Mz-ChA-1) grown as monolayers (2D) or multicellular tumor spheroids (3D). MiRNA profiling was performed using NanoString technology. Predicted targets were analyzed by over-representation analysis, and selected miRNAs and genes were validated by RT-qPCR and ELISA-based assays. RESULTS: 3D growth induced extensive miRNA remodeling, with distinct (54 deregulated in Sk-ChA-1 and 29 in Mz-ChA-1 cells) and partially overlapping signatures (miR-1283, miR-577, and miR-2113). Among the shared miRNAs, predicted targets included DUSP10 and RBFOX1, while in spheroids, cell-specific multiple miRNAs converged on shared targets (TNRC6B, SMARCAD1, ATG14, HMGA2, and CLOCK) displaying inverse expression patterns. The transcriptional program impacted MAPK signaling, enhanced EMT, and activated stress-adaptive networks but attenuated proliferation in 3D Sk-ChA-1 cells, while Mz-ChA-1 cells retained a more epithelial and proliferative profile. In this context, we point out the involvement of miR-19b-3p using anti-miR transfection experiments. CONCLUSION: Our findings reveal a miRNA-driven regulatory landscape associated with 3D growth in eCCA, linking tumor architecture to signaling rewiring and cellular plasticity, and highlight potentially druggable candidate targets and pathways to investigate as candidates using inhibitors or gene therapy-based interventions.

Humans↗
PubMed1992

Establishment and characterization of a human papillary thyroid carcinoma cell line with oxyphilic differentiation (ONCO-DG 1).

In the present study the establishment and characterization of a new oxyphilic papillary thyroid carcinoma cell line--ONCO-DG1- is given. With immunohistological, histochemical and flow cytometric methods, ONCO-DG 1 cells revealed features of epithelial differentiation. Furthermore the cells formed von Kossa-positive deposits resembling psammoma bodies in monolayer and spheroid culture until late passages. The tumor cell line is now in the 40th subculture. Because of the ability to form multicellular tumor spheroids (MCTS), this cell line is a good model for examining the interaction between thyroid tumor cells and confluent human endothelial cells on extracellular matrix in vitro. It is also suitable for xenotransplantation studies, because it is tumorigenic in NMRI nude mice in vivo.

Animals↗
PubMed1992

Variations in tumor cell growth rates and metabolism with oxygen concentration, glucose concentration, and extracellular pH.

Tumors and multicellular tumor spheroids can develop gradients in oxygen concentration, glucose concentration, and extracellular pH as they grow. In order to calculate these gradients and assess their impact on tumor growth, it is necessary to quantify the effect of these variables on tumor cell metabolism and growth. In this work, the oxygen consumption rates, glucose consumption rates, and growth rates of EMT6/Ro mouse mammary tumor cells were measured at a variety of oxygen concentrations, glucose concentrations, and extracellular pH levels. At an extracellular pH of 7.25, the oxygen consumption rate of EMT6/Ro cells increased by nearly a factor of 2 as the glucose concentration was decreased from 5.5 mM to 0.4 mM. This effect of glucose concentration on oxygen consumption rate, however, was slight at an extracellular pH of 6.95 and disappeared completely at an extracellular pH of 6.60. The glucose consumption rate of EMT6/Ro cells increased by roughly 40% when the oxygen concentration was reduced from 0.21 mM to 0.023 mM and decreased by roughly 60% when the extracellular pH was decreased from 7.25 to 6.95. The growth rate of EMT6/Ro cells decreased with decreasing oxygen concentration and extracellular pH; however, severe conditions were required to stop cell growth (0.0082 mM oxygen and an extracellular pH of 6.60). Empirical correlations were developed from these data to express EMT6/Ro cell growth rates, oxygen consumption rates, and glucose consumption rates, as functions of oxygen concentration, glucose concentration, and extracellular pH. These empirical correlations make it possible to mathematically model the gradients in oxygen concentration, glucose concentration, and extracellular pH in EMT6/Ro multicellular spheroids by solution of the diffusion/reaction equations. Computations such as these, along with oxygen and pH microelectrode measurements in EMT6/Ro multicellular spheroids, indicated that nutrient concentration and pH levels in the inner regions of spheroids were low enough to cause significant changes in nutrient consumption rates and cell growth rates. However, pH and oxygen concentrations measured or calculated in EMT6/Ro spheroids where quiescent cells have been observed were not low enough to cause the cessation of cell growth, indicating that the observed quiescence must have been due to factors other than acidic pH, oxygen depletion, or glucose depletion.

Animals↗