Multicellular spheroids

Abstract

Cellular aggregates have been used in developmental biology and in experimental cancer research for several decades. Spherical aggregates of malignant cells, i.e. multicellular tumor spheroids, may serve as in vitro models of tumor microregions and of an early, avascular stage of tumor growth. The similarities between the original tumor and the respective spheroids include volume growth kinetics, cellular heterogeneity, e.g. the induction of proliferation gradients and quiescence, as well as differentiation characteristics, such as the development of specific histological structures or the expression of antigens. Research using cell aggregates has been focussed on mechanisms involved in the control of proliferation, invasion and metastasis. Immunological studies with spheroids have resulted in the characterization of defense cells which are responsible for specific host-versus-tumor reactions. The vast majority of investigations on spheroids concerns the simulation of therapy with regard to various treatment modalities, combination treatments and systematic analyses of using various endpoints in predictive assays. Only a few pathophysiological studies on the interrelationship among tumor-specific micromilieu, cellular metabolism, proliferative status, and cellular viability have been undertaken with the spheroid model up to now. Since these studies are indicative of a large influence of the cellular microenvironment on basic biological properties of cancer cells, investigations of these epigenetic mechanisms should be intensified in future research on cell aggregates. Similarly, the molecular basis of the biological peculiarities found in malignant cells grown as three-dimensional aggregates has to be investigated more intensively.

Continuously perfused microbubble array for 3D tumor spheroid model

“…2,3 Hence, the application of multi-cellular tumor spheroids ͑MCTSs͒ as a primary tool in anti-tumor drug development has been proposed by numerous researchers. [4][5][6][7][8][9] MCTSs represent a complexity level beyond monolayers of cells in which hypoxic and necrotic cells are surrounded by highly aggressive, metastatic cells. This tumor spheroid structure more closely resembles in vivo tumors, which provides insights into the growth of tumors as well as the complexity of the tumor microenvironment.…”

Growth‐related changes of oxygen consumption rates of tumor cells grown in vitro and in vivo

“…These proteins probably are part of several stress protein systems which enable cells to survive under unfavourable environmental conditions (Subjeck and Shyy, 1986). The structural changes observed are attributed to a deprivation of oxygen, principal substrates and growth factors which usually are concomitant with an accumulation of metabolic waste products, such as lactate or ammonia, and the appearance of dead cells (for reviews see Mueller-Klieser, 1987, Sutherland, 1988 (Mueller-Klieser et al, 1986b). Since one gram of ascites cells contained (7.8 2 0.5) .…”

Acquired multicellular-mediated resistance to alkylating agents in cancer.

“…All assays were done in triplicate with consistent results. necessary to recapitulate this type of growth (7,8,13). For example, sensitivity of tumor cells to radiotherapy can be strongly affected by hypoxic regions (5, 7).…”

“…Similarly, the ability of certain cytotoxic drugs or antibodies (or drugantibody conjugates) to kill tumor cells can be limited because of the necessity of having to penetrate deeply into tumor nodules (5, 7). Thus, performing chemosensitivity or radiosensitivity assays on tumor cells grown only in monolayer culture can sometimes provide misleading information with respect to the situation in vivo (7,8,13). There are several methods that can be used to obtain three-dimensional growth of carcinoma cell lines that normally grow as attached monolayers (7, 13)-e.g., by growth in spinner flasks or on plastic surfaces coated with a thin layer of 1% agarose where attachment to the plastic surface is prevented (7,13).…”