Dual effect of KrasD12 knockdown on tumorigenesis: increased immune-mediated tumor clearance and abrogation of tumor malignancy

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Abstract
Activating mutations in the human KRAS proto-oncogene are acquired during the earliest stages of colorectal cancer development. If mutant KRAS is to be used as a target for therapy in colorectal cancer, tumor growth should depend on its continued presence. Here, we report that stable knockdown of KrasD12 in murine C26 colorectal cancer cells by RNA interference resulted in loss of transformed properties in vitro. The incidence of subcutaneous tumor formation was reduced by 60% and the lag time was increased sevenfold. KrasD12-knockdown tumors grew noninvasively and did not cause morbidity. Remarkably, some of the KrasD12-knockdown tumors regressed spontaneously, which rendered these mice resistant to parental C26 tumor growth. In immune-deficient hosts, the incidence of tumor formation by KrasD12-knockdown cells was 100%. None of these tumors regressed spontaneously. We conclude that the reduced incidence of tumor formation by KrasD12-knockdown cells is due to tumor cell clearance by the host immune system, but not to an intrinsic inability of these cells to grow out as tumors. Interestingly, KrasD12 knockdown resulted in increased production of interleukin 18 (Il-18), an immune-stimulatory cytokine that has been implicated in limiting colorectal tumor formation. Thus, mutant KrasD12 suppresses Il-18 production in colorectal tumor cells, which may contribute to evasion of the local immune system during tumor development.