Modulation of the immune response and tumor growth by activated Ras

Abstract

As a result of its transforming abilities, activated Ras is expressed in a great number of cancers. The ras mutation frequency varies between 95% in pancreatic cancer and 5% in breast cancer. In leukemia, the highest frequency (30%) is found in acute myeloid leukemia. The presence of ras mutations has been correlated with a poor prognosis and negative clinical outcome. This suggests that mutated Ras activates mechanisms, which favor tumor growth, enhance the metastatic capacity of tumors or modulate tumor-specific immune responses. Several new functions of Ras, such as downregulation of major histocompatibility complex molecules, upregulation of certain cytokines, growth factors and degradative enzymes have been uncovered in the last decade. Additionally, mutated Ras can also serve as a primary target for the development of immunotherapy or drug therapy. This review will discuss the mechanisms by which Ras expressing tumors are able to evade destruction by the immune system and enhance their growth and metastatic potential. It will further elaborate on the attempts to develop successful immunotherapy and drug therapy targeting Ras expressing tumors.

Molecular signals in anti-apoptotic survival pathways

“…8 Receptor-activated Ras relays extracellular signals through signal transduction pathways, mediating multiple intracellular responses including growth, survival, apoptosis and regulation of the immune response. [9][10][11] Ras signalling and conversion between its GTP-and GDP-bound forms is a tightly regulated event, orchestrated primarily by guanine-nucleotide exchange factors (GEFs) 12 and GTPaseactivating proteins (GAPs), 13 positive and negative regulators of Ras, respectively. Ras is one of the most frequently deregulated proteins in leukaemias, estimated to be mutated in at least 30% of cases.…”

“…Oncogenic Ras signalling influences tumorigenesis, not only due to increased proliferation, but also due to the increased ability of Ras to suppress apoptosis. 9,11 There remains much controversy as to the precise significance of Ras in leukaemia. The high incidence of Ras mutations in the pre-leukaemic disorder, myelodysplasia, suggests that Ras mutations are an initiating event in leukaemias.…”

“…24 Despite extensive debate, Ras deregulation is accepted as contributing to disease aggression, immune evasion and reduced patient survival. 11 Patients with N-Ras mutations have a poor response to chemotherapy and low remission rates. 25 …”

“…Ras also lies at the pinnacle of many separate signal transduction pathways 9,11 (Figure 1). Modifications in Ras signalling would alter each of these downstream kinase cascades, permitting amplification of deregulated signals and potentially inducing oncogenesis.…”

Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals

“…19 Despite this debate, deregulation of Ras or its signalling pathways is considered to contribute to disease aggression, chemoresistance, immune evasion and reduced patient survival. 15,20 Furthermore, Ras is reputed to upregulate expression of the viability promoting molecule Bcl-2 21 often elevated in myeloid leukaemias 22 where it promotes tumour survival, contributes to drug resistance and is considered a poor prognostic marker for clinical outcome. 23 A recognised distinction has been made between mitogenic and survival pathways, in that many previously recognised mitogens are now considered to be survival factors, promoting survival separately from proliferation, eg IL-3.…”