Tumor Cell Rejection Through Terminal Cell Differentiation

Abstract

Leukemic cells cultured in the presence of various conditioned media differentiate into macrophages. This finding suggested that the maintenance of undifferentiated state and self-renewal in vivo may be related to the inability of the host to generate an appropriate level of differentiation factor (DF). Evidence for this hypothesis was derived from experiments in vitro and in vivo with myeloid leukemia of rat. The following results were obtained: (i) in vitro, the percentage of cell differentiation at a fixed concentration of DF was inversely related to the concentration of cells; (ii) leukemic cell inoculates that were lethal to 7-day-old rats were rejected by 21-day-old rats; (iii) leukemic cells in diffusion chambers underwent differentiation in 21-day-old rats but not in 7-day-old rats; (iv) organs from 21-day-old rats contained more DF activity than those of 7-day-old rats; (v) treatment of rats with DF in diffusion chambers resulted in leukemic cell differentiation inside the chamber; and (vi) the development of leukemia in 7-day-old rats was aborted by treatment with DF. These results show that the differentiation of rat leukemia cells requires the appropriate level of DF. The proliferation of transplanted leukemia cells in 7-day-old rats goes unchecked because of inadequate generation of DF. Conversely, in the 21-day-old rats, rejection is accomplished by differentiation of the transplanted cells.

Aloe-emodin as antiproliferative and differentiating agent on human U937 monoblastic leukemia cells

“…By and large, most of the differentiation agents studied to date have demonstrated significantly less toxicity as compared to standard cancer treatments. Indeed, differentiation therapy is an approach to the treatment of advanced or aggressive malignancies and showed significant efficacy in the treatment of many types of cancer (Jimenez and Yunis, 1987). We have recently demonstrated that AE, a hydroxyanthraquinonic compound present mostly in A. barbadensis Miller leaves and in Rheum palmatum L. roots, possesses a differentiative potential on melanoma cells (Tabolacci et al, 2010a).…”

A role for endogenous reverse transcriptase in tumorigenesis and as a target in differentiating cancer therapy

“…Both of these processes yield the expansion of a malignant cell population, characterized by a high proliferative potential and a low differentiation state. In this light, the pathological features of transformed cells can be reversed by pharmacological treatments capable of restoring a differentiated phenotype, rather than inducing cytotoxicity, in transformed cells (Sachs, 1978;Fisher and Grant, 1985;Jiminez and Yunis, 1987): this emerging strategy aims at tumor reversion using compounds that ''force'' tumor cells to re-enter the terminal differentiation program through a process termed ''differentiation therapy.'' Retinoic acid is the prototype agent of this kind, a classical morphogen in embryo development and an active inducer of differentiation, first fractionated from anticancer remedies in traditional chinese medicine, now widely used to treat leukemia of several types.…”

15-Lipoxygenase-1 as a tumor suppressor gene in colon cancer: is the verdict in?

“…Loss of the ability to undergo normal cell differentiation is one of the important mechanisms of tumorigenesis [40,41]; cell differentiation, especially terminal cell differentiation, often becomes aberrant in cancer [42,43]. Efforts are being made to develop anticancer therapeutic interventions to restore terminal differentiation in cancer cells [43–46].…”