Lung cancer is leading the worldwide cancer related deaths. It can be divided into to two main types: Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC), the later accounting for 80% of the cases. Common genetic alterations associated with lung cancer are the loss of tumor suppressors, like p53, LKB1 etc. and activating mutations, overexpression, amplification of oncogenes, such EGFR and K-RAS. In lung tumors, EGFR signals through K-RAS, PI3K and STAT3. STAT3 regulates important pathways in tumorigenesis, through upregulation of genes encoding apoptosis inhibitors (BCL-XL, BCL-2, MCL-1 and survivin). In patient samples and NSCLC cell lines nuclear pSTAT3 is upregulated and correlates with subsequent suppression of apoptosis of NSCLC tumors; however, the role of STAT3 in lung cancer in vivo has not yet been investigated. We have established a genetic mouse model that allows to induce K-RAS-dependent lung tumors and simultaneously genetically ablates STAT3.
Human samples of lung adenocarcinoma stained with an antibody against STAT3. This example shows an STAT3 immunohistochemistry of human lung adenocarcinoma samples. Lung adenocarcinoma patients expressing high levels of STAT3 in the tumors (A) have a better prognosis that those patients expressing low levels of STAT3 in the tumors (B)
Analysis of this model showed that mice with deleted STAT3 and activated K-RAS have a shorter life span when compared to control animals (K-RAS activated, STAT3 proficient). Furthermore, animals with deleted STAT3 and activated K-RAS have a significant increase in tumor burden and develop more adenomas and adenocarcinomas than the control animals. Further analysis of this model revealed that STAT3 supresses NFkB-dependent IL-8 induction, myeloid tumor infiltration and tumor vascularization and therefore, tumor growth. Treating the animals with IL-8 blocker rescued the increased tumorigenesis observed in STAT3 deficient mice. Moreover, suppression of STAT3 in a xenografted human lung adenocarcinoma cell line promotes tumorigenesis and lung cancer patients expressing low levels of STAT3 in the tumors present a bad prognosis. This data suggest that STAT3 suppress KRAS-induced lung tumorigenesis and identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant adenocarcinoma with therapeutic and prognostic relevance (Grabner et al., Nature Communications 2015).
Functions of STAT3 in KRAS-mutant cancer cells. (A) Upon activation of signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NFκB) is retained in the cytoplasm, therefore STAT3 inhibits the expression of chemokine (C-X-C motif) ligand 1 (CXCL1)/interleukin-8 (IL-8). (B) In the absence of STAT3, enhanced NFκB activity induces increased expression of chemokine CXCL1/IL-8 in KRAS-mutant tumors. CXCL1 attracts tumor supportive myeloid cells and promotes angiogenesis thereby enhancing tumor growth and progression (from Grabner et al. Mol.Cell. Oncol. 2016 May; 3(3) )