ACTION OF POLYPEPTIDE GROWTH FACTORS IN COLON CANCER; DEVELOPMENT OF NEW THERAPEUTIC APPROACHES

Subhas Chakrabarty, Sharon Reynolds, Hong mei Wang and Sriram Rajagopal

Division of Laboratory Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030

Received 9/3/97 Accepted 9/15/97

2. INTRODUCTION

Metastatic human colon cancer is a highly refractory malignant disease which afflicts both men women in equal proportion. The antimetabolite, 5-fluorouracil (5-FU), used to treat colon cancer over 4 decades ago, is still the drug of choice today for the treatment of metastatic disease. Despite some improvements in adjuvant therapy using 5-FU in combination with leucovorin or levamisole, almost half of all colorectal cancer patients will die of metastatic disease (1). Therefore, new therapeutic approaches must be explored to improve survival. An understanding of the biology behind malignant transformation and the mechanisms sustaining the transformed phenotype may provide avenues of therapeutic intervention.

Control of cellular proliferation, differentiation and adhesion are complex biological processess in which different biological systems interact to achieve control. Cell-matrix and cell-cell adhesion are important cellular processess in regulating cellular proliferation and differentiation (2-5). Extracellular matrix (ECM) adhesion molecules modulate gene expression in epithelial cells in a tissue specific manner (5-7). Disruption of these processes is a hallmark of malignant transformation and plays a critical role in tumor progression and the behavior of malignant cells (8-10).

Polypeptide growth factors constitute a potent class of extracellular and/or intracellular signal molecules in regulating cellular proliferation and differentiation (11-13). Aberrant expression of growth factors and/or aberrant responses to growth factors may circumvent the normal pathway of differentiation, leading to cellular transformation, tumor progression and maintenance of the transformed phenotype (11, 14). Transforming growth factor (TGF) beta constitutes a class of multi-functional polypeptide growth factors that regulate proliferation and differentiation in many cell types (15-17) and suppress malignancy in TGF-beta-responsive epithelial cancer cells (18-20). Loss of responsiveness to TGF-beta is thought to be a mechanism of escape from normal growth control in malignant cells (21-22). The ability of TGF-beta to induce a more benign and differentiated phenotype in malignant cells is partly attributable to its ability to upregulate the synthesis of ECM adhesion molecules (23-28). Thus, TGF-beta may be viewed as a class of negative growth factors.

The epidermal growth factor (EGF) family of polypeptide growth factors such as EGF and TGF-alpha, on the other hand, are potent stimulators of cellular proliferation and stimulate the malignant behavior of many epithelial-derived cancer cells (29-35). Thus, the EGF family of growth factors may be viewed as a class of positive growth factors. How ECM adhesion molecules and growth factors interact in controlling proliferation, differentiation and adhesion is depicted in Figure 1.

Figure 1. Interaction of ECM adhesion molecules with growth factors

In this review, we will discuss how negative and positive growth factors act in colon cancer and review the rationale and strategy behind the development of new therapeutic approaches. Where appropriate, the biologic similarities or differences by comparison with other tumor types or other agents involved in regulating differentiation will also be discussed.