The multilayered postconfluent cell culture as a model for drug screening

Padrón, José M.; Wilt, C.L. van der; Smid, Kees; Smitskamp‐Wilms, E.; Backus, H. H. J.; Pizao, Paolo E; Giaccone, Giuseppe; Peters, Godefridus J.

doi:10.1016/s1040-8428(00)00083-4

Cited by 78 publications

(58 citation statements)

References 64 publications

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“…This work again implicates the collage network and collagen-binding GAGs as factors in hindering the interstitial diffusion of macromolecules. Multicellular spheroids and multilayer cellular sandwiches/ membranes are being used to test the penetrability and effectiveness of therapeutics (Fracasso and Colombatti, 2000;Padron et al, 2000;Johnson et al, 2001). Since these in vitro systems do not have the host stromal cells, the present work shows that caution must be exercised in extrapolating the results obtained from these systems to tumours in vivo.…”

Section: Discussionmentioning

confidence: 91%

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

et al. 2002

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The tumour extracellular matrix acts as a barrier to the delivery of therapeutic agents. To test the hypothesis that extracellular matrix composition governs the penetration rate of macromolecules in tumour tissue, we measured the diffusion coefficient of nonspecific IgG in three rhabdomyosarcoma subclones growing as multicellular spheroids in vitro or as subcutaneous tumours in dorsal windows in vivo. In subcutaneous tumours, the diffusion coefficient decreased with increasing content of collagen and sulphated glycosaminoglycans. When grown as multicellular spheroids, no differences in either extracellular matrix composition or diffusion coefficient were found. Comparison of in vitro vs in vivo results suggests an over-riding role of host stromal cells in extracellular matrix production subjected to modulation by tumour cells. Penetration of therapeutic macromolecules through tumour extracellular matrix might thus be largely determined by the host organ. Hence, caution must be exercised in extrapolating drug penetrability from spheroids and multilayer cellular sandwiches consisting of only tumour cells to tumours in vivo. British Journal of Cancer (2002) The extracellular matrix (ECM) is a potent barrier to the delivery and penetration of complex biopharmaceuticals such as monoclonal antibodies, therapeutic proteins, or genes. Due to the elevated interstitial fluid pressure in tumours , the therapeutic agents must reach the tumour cells by interstitial diffusion. It is not clear whether the network of fibrillar collage or the glycosaminoglycan (GAG) gel plays the most important role in limiting the diffusion of macromolecules through the ECM, and what the role of the host stromal cells is. Netti et al (2000) found that the amount of collagen in tumours correlated inversely with the diffusion coefficient of macromolecules, and collagenase treatment of the tumour increased the diffusion coefficient. Pluen et al (2001) provided further support for the role of collagen by measuring diffusion in tumours grown in subcutaneous tissue and the cranium. Hyaluronidase, on the other hand, is reported to reduce the diffusion coefficient of albumin in lung interstitium (Qiu et al, 1999).We postulated that diffusion of macromolecules is hindered both by the collagen network and by the hydrophilic gel of GAG and proteoglycans. To test this hypothesis we used three distinct clones with different degrees of differentiation and ECM (Groeschel et al, 1994) derived from a rat rhabdomyosarcoma, growing as multicellular spheroids in vitro or subcutaneously in dorsal chambers in mice in vivo. The production of ECM in tumours is the result of an active interaction between the tumour cells and stromal cells of the host (Gullino and Grantham, 1962;Knudson et al, 1984), whereas the extracellular matrix of multicellular spheroids is solely produced by the tumour cells. Comparison of the ECM composition in tumours growing as xenografts in vivo and as multicellular spheroids in vitro, is likely to reveal the influence of the host stromal ce...

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Section: Discussionmentioning

confidence: 91%

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

et al. 2002

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“…As for normal tissues, culture models may be more or less complex, and reflect, more or less accurately, the in vivo specificities of the native tissue. Briefly, from the simpler to the more complex in vitro models, biological studies can be performed on isolated subcellular fractions, microsomes, single isolated cells, cells in suspensions, 2D cultured cells (homotypic or heterotypic cultures), and 3D cultures (multilayered confluent cells, multicellular spheroids, with or without scaffolds, in mono-or heterotypic configurations, tissue slices, organotypic systems) [69,75,76]. Often, the more the system model is simplified, the less it is able to maintain, at long-term, cells' viability and functions.…”

Section: D Versus 3d Cancer Modelsmentioning

confidence: 99%

In Vitro Modeling of Tissue-Specific 3D Microenvironments and Possibile Application to Pediatric Cancer Research

Pizzimenti¹

2014

J. Pediatr. Oncol.

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A large body of evidence indicates that three dimensional (3D) cancer models are superior to two-dimensional (2D) ones in better representing the in vivo phenomena. Indeed, 3D models allow recapitulating in vitro the in vivo features observed in solid tumors (e.g. cell polarity, cell-cell/cell-matrix interactions, biochemical/metabolic gradients, anchorage-independent growth and hypoxia). Moreover, it is well established that the microenvironment plays a fundamental role in regulating tumor development and behavior, including drug resistance. Thus, innovative models able to mimic this complexity represent attractive tools in cancer research. In this review article, we provide a comprehensive review of the application of 3D culture systems in pediatrics' cancer research. In particular, 3D in vitro/ex vivo models of the most common pediatric tumors, such as leukemias, lymphomas and malignancies of the nervous system, will be considered.

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“…Multicellular spheroids (MCS) and other 3-D culture systems mimic human solid tumors better than 2-D monolayer cultures [8][9][10][11]. MCS are known to be more resistant to drug effects compared to monolayer cultures [12][13][14][15] and many clinically used drugs show limited potency on spheroids [1,16,17].…”

Section: Introductionmentioning

confidence: 99%

Massive induction of apoptosis of multicellular tumor spheroids by a novel compound with a calmodulin inhibitor-like mechanism

Mohanty¹,

Fayad²,

Olofsson³

et al. 2013

J Cancer Ther Res

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The multilayered postconfluent cell culture as a model for drug screening

Cited by 78 publications

References 64 publications

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

In Vitro Modeling of Tissue-Specific 3D Microenvironments and Possibile Application to Pediatric Cancer Research

Massive induction of apoptosis of multicellular tumor spheroids by a novel compound with a calmodulin inhibitor-like mechanism

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