Tumor reversion: correction of malignant behavior by microenvironmental cues

Abstract

Cancer is characterized by unrestrained proliferation and loss of organization, a process that is intimately linked to, and controlled by, reciprocal signaling between the genetically altered tumor epithelium, the stroma, the components of the basement membrane and inflammatory mediators. Much work has been done to characterize the genetics of cancer cells. In this review, we describe the experiments that have been performed, which point to the significant role of the tissue microenvironment in the developmental regulation of normal and neoplastic cells. Using a variety of model systems, the works of a number of laboratories have converged on a hypothesis where the correction of 1 or 2 signaling defects can revert tumor cells to a normal phenotype, both in vivo and in culture, even when the tumor cells possess multiple genetic and epigenetic lesions. This paradigm has been successfully used to treat acute promyelocytic leukemia, and it remains the task of biomedical researchers to identify additional targets for the reversion of other human malignancies.

FIGURE 1

A schematic diagram of the experiments of Mintz and Illmensee demonstrating that the malignant potential of teratocarcinoma (129) cells could be constrained during embryogenesis, and that the resulting mice contained tumor-free tissues derived from the teratocarcinoma cells. Briefly, a solid metastatic teratoma was produced by placing a 6-day-old 129 embryo under a testis capsule. An ascites tumor of embryoid bodies was subsequently established and maintained by transplantation for 200 generations. The central core cells of the embryoid bodies were injected into the blastocysts of C57BL/6 mice, which were then transferred to pseudopregnant mothers. Chimeric mice were obtained, in which cells of the 129 genotype had made significant contributions to the coat and other tissues. Subsequent breeding of one such male mouse showed that it produced viable sperm of the 129 genotype. Despite having been derived from malignant cells, these mice did not develop tumors. Reproduced with modifications from Mintz and Illmensee.

FIGURE 2

Contribution of v-Src-infected cells to normal structures during chick embryo development. Chick limb buds were infected at day 4 in ovo (embryonic stage 24) with a virus encoding v-Src and a genetic marker, beta-galactosidase. The contribution of v-Src-infected cells to normal tissues (in this case a day 14 feather filament) is revealed by X-gal staining of embryo whole mounts (data not shown; see also Stoker et al.15).

FIGURE 3

Growth arrest and restoration of polarity in malignant T4-2 cells in response to inhibition of β1-integrin. Phenotypically normal S1 cells form polarized growth-arrested acinar structures in 3D lrBM culture, while their malignant counterparts, T4-2, form disorganized continuously proliferating colonies. Culture of T4-2 cells in 3D lrBM in the presence of a function-blocking antibody to β1-integrin leads to growth arrest, reorganization of the actin cytoskeleton and adherens junctions and restoration of apicobasal polarity. Scale bar = 10 µm. Reproduced with modifications from Weaver et al.