Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival

Abstract

Metastasis underlies the majority of cancer-related deaths. Thus, furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. Epithelialto-mesenchymal transitions (EMTs) endow carcinoma cells with enhanced migratory and survival attributes that facilitate malignant progression. Characterization of EMT effectors is likely to yield new insights into metastasis and novel avenues for treatment. We show that the presence of the receptor tyrosine kinase Axl in primary breast cancers independently predicts strongly reduced overall patient survival, and that matched patient metastatic lesions show enhanced Axl expression. We demonstrate that Axl is strongly induced by EMT in immortalized mammary epithelial cells that establishes an autocrine signaling loop with its ligand, Gas6. Epiallelic RNA interference analysis in metastatic breast cancer cells delineated a distinct threshold of Axl expression for mesenchymal-like in vitro cell invasiveness and formation of tumors in foreign and tissue-engineered microenvironments in vivo. Importantly, in two different optical imagingbased experimental breast cancer models, Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and several major organs and increased overall survival. These findings suggest that Axl represents a downstream effector of the tumor cell EMT that is required for breast cancer metastasis. Thus, the detection and targeted treatment of Axl-expressing tumors represents an important new therapeutic strategy for breast cancer.carcinoma | receptor tyrosine kinase | breast cancer

An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies

“…Here we showed that YW327.6S2 is able to reduce the metastasis of MDA-MB-231 breast cancer cells to the bone. These results are consistent with our previous data that silencing of Axl by RNAi in breast cancer cells inhibits their metastasis to the lung in an orthotropic model (Li et al, 2009;Gjerdrum et al, 2010), suggesting that this anti-Axl antibody could have therapeutic potential not only in the treatment of primary tumor but also in metastatic disease.…”

“…Previous studies have established the role of Axl in promoting tumor cell migration, invasion and metastasis (Vajkoczy et al, 2006;Tai et al, 2008;Zhang et al, 2008;Li et al, 2009;Gjerdrum et al, 2010). Here we showed that YW327.6S2 is able to reduce the metastasis of MDA-MB-231 breast cancer cells to the bone.…”

Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer

“…Gas6-activated Axl signaling marshalls important downstream regulators of cell motility such as Rac and Akt (Allen et al, 2002;Hasanbasic et al, 2004) and regulates haptotaxis toward vitronectin in endothelial cells (Holland et al, 2005). Recent studies support a role for Axl as a regulator of glioma, breast, lung and pancreatic tumor cell migration (Shieh et al, 2005;Vajkoczy et al, 2006;Koorstra et al, 2009) and very recently Axl was identified as an important regulator of breast cancer metastasis and survival of patients (Vajkoczy et al, 2006;Gjerdrum et al, 2010). We found that vimentin regulates Axl expression in breast cancer cell lines.…”

LAMC2 enhances the metastatic potential of lung adenocarcinoma

“…The receptor tyrosine kinase AXL is an oncogene shown to promote tumor cell growth, metastasis, and drug resistance to HER2 and epithelial growth factor receptor-targeted therapy. [22][23][24][25] LAMC2 expression has been shown to be associated with prognosis in several solid tumors, 5,9-14 but its role in the metastatic process is not clear.…”