Oncogenic ras-induced expression of cytokines: a new target of anti-cancer therapeutics

Abstract

The Ras family of small guanosine triphosphatases normally transmit signals from cell surface receptors to the interior of the cell. Stimulation of cell surface receptors leads to the activation of guanine exchange factors, which, in turn, convert Ras from an inactive GDP-bound state to an active GTP-bound state. However, in one third of human cancers, RAS is mutated and remains in the constitutively active GTP-bound state. In this oncogenic state, RAS activates a constellation of signaling that is known to promote tumorigenesis. One consequence of this oncogenic RAS signal in cancer cells is the upregulation of the cytokines interleukin (IL)-6, IL-8, and chemokine growth-regulated oncogene 1 (GRO-1). We review the evidence supporting a role for these cytokines in oncogenic RAS-driven solid tumors.

Figure 1

Inhibiting cytokine function impedes oncogenic Ras-driven tumor growth. Oncogenic Ras-mediated activation of cytokine gene transcription (double helix) in tumor cells (brown oval) leading to increased cytokine mRNA (purple wavy line) and protein (blue spheres) can be blocked by A) knock out of the cytokine gene, B) RNAi targeting the cytokine mRNA or C) cytokine neutralizing antibodies inhibits tumor growth.

Figure 2

Oncogenic Ras stimulated cytokine secretion promotes tumor growth. Oncogenic Ras (Ras-GTP) promotes the transcription of cytokine genes (double helix), leading to elevated levels of secreted cytokines (blue spheres) that act to modulate the immune system (yellow cells), promote angiogenesis (purple capillaries) and activate tumor stroma (blue cells).