Department of Pharmacology and Therapeutics
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo NY USA 14263
Tel: 716 - 845 - 3212
E-mail: alexander.bloch@roswellpark.org

Current Program
Differentiation, Cell Cycle Controls
Tumor cells are arrested at incomplete stages of maturation, while retaining their ability to proliferate at such stages. As a result, they give rise to populations of immature "cancer" cells that lack functionality. A promising approach towards ameliorating this deficiency is to force the terminal differentiation of the maturation arrested cells. Differentiation-inducing cytokines and drugs that can activate the differentiation process at diverse stages of the maturation path, have shown promise for achieving that objective. Our program is aimed at identifying agents that are effective differentiation inducers, and at determining the molecular mechanisms by which they stimulate tumor cell maturation.

Progress
Using ML-1 human myeloblastic leukemia cells, we have identified the conditions required for their growth or differentiation in serum-free medium. IGF-1 and transferrin stimulate their growth, whereas TGFb 1 or TNFa induce their differentiation to monocytes. Administered jointly, the two cytokines induce the formation of macrophage-like cells. Initiation of proliferation, but not of differentiation, is followed by an approximately 20-25 fold increase in the nuclear level of the DNA processivity factor PCNA and of the proliferation-specific transcription factor E2F1. In contrast, induction of differentiation, but not of proliferation, is accompanied by a 25-30 fold increase in the nuclear level of the growth suppressor proteins p53, pRb, p130, and p21, these proteins interacting to inhibit the expression and activation of PCNA and of E2F1. As a result G1/S associated DNA and mRNA synthesis is inhibited, growth is uncoupled from differentiation, and the maturation program allowed to proceed . Where this function of the suppressor proteins is impaired, the capacity for differentiation is lost, and proliferation at an incomplete stage of development proceeds, that condition being the prime characteristic of the cancer cell.

Key Publications

• Zhan-Rong Li, Rosemary Hromchak, Anuradha Mudipalli, and Alexander Bloch. Tumor suppressor proteins as regulators of cell differentiation. Cancer Res. 58:4282-4287, 1998.