The transient and constitutive inflammatory signaling in tumorigenesis

It is estimated that about 25% of cancers appear due to chronic infection or other types of chronic inflammation. However, almost all cancers have abnormal or/and constitutive inflammatory signaling activation. Much progress has been made in elucidating the mechanisms by which inflammatory signaling drives tumor progression and metastasis. However, how the abnormal and constitutive inflammatory signaling is initiated and maintained in transforming cells, and its roles in the early stages of tumorigenesis, such as cell transformation, are largely unknown. In a recent study, we established an in vitro co-culture cell transformation system. Using this system we discovered that a constitutively activated, feedforward inflammatory signaling circuit normally harnessed by miR-200c is established during cell transformation, and that this circuit plays crucial roles in cell transformation and tumorigenesis. This circuit is comprised of IL6, miR-200c, PTPRZ1 and JNK2 and the transcription factors HSF1, estrogen receptor (ERα), ZEB1, p65/RelA and c-Jun (Fig. 1A). Importantly, this constitutive inflammatory signaling circuit is manifest in human cancer cells and in ErbB2 (Neu)-driven breast cancer transgenic mouse models, where deletion of IL6 disables this circuit and dramatically impairs mammary tumorigenesis. The feedforward nature of this constitutive inflammatory signaling circuit provides explanations for the common phenomenon that many (inflammatory) signaling pathways are interplayed and simultaneously constitutively activated in the same cancer cells. It also demonstrated that the cause and maintenance of the constitutive activation of inflammatory The transient and constitutive inflammatory signaling in tumorigenesis