Pathogenesis of RON receptor tyrosine kinase in cancer cells: activation mechanism, functional crosstalk, and signaling addiction

The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor im- plicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor over- expression, generation of structure-defected variants, and point mutations in the kinase domain contribute to RON signaling activation. Recently, functional crosstalk between RON and signaling proteins such as MET and EFGR has emerged as an additional mechanism for RON activation, which is critical for tumorigenic develop- ment. The RON signaling crosstalk acts either as a regulatory feedback loop that strengthens or enhances tumor- igenic phenotype of cancer cells or serves as a signaling compensatory pathway providing a growth/survival ad- vantage for cancer cells to escape targeted therapy. Moreover, viral oncoproteins derived from Friend leukemia or Epstein-Barr viruses interact with RON to drive viral oncogenesis. In cancer cells, RON signaling is integrated into cellular signaling network essential for cancer cell growth and survival. These activities provide the mo- lecular basis of targeting RON for cancer treatment. In this review, we will discuss recent data that uncover the mechanisms of RON activation in cancer cells, review evidence of RON signaling crosstalk relevant to cancer malignancy, and emphasize the significance of the RON signaling addiction by cancer cells for tumor therapy. Understanding aberrant RON signaling will not only provide insight into the mechanisms of tumor pathogenesis, but also lead to the development of novel strategies for molecularly targeted cancer treatment.

Rare giant asymptomatic skull metastasis from intrahepatic cholangiocarcinoma

To the Editor:Skull metastases are common cranial tumors in adults.Breast cancer,lung cancer,prostate cancer and malignant lymphoma are the most common types of primary tumor.Skull metastases are often asymptomatic;however,they can also cause local pain and cranial nerve palsies,and even severe disability due to compres-sion of the dural sinuses[1].In these cases,surgery is necessary to improve the patients'quality of life,especially relieving the mass effect of skull metastasis.Skull metastases from less common ma-lignant tumors such as intrahepatic cholangiocarcinoma(ICC)have rarely been described[2–6],and its treatment still remained a big challenge for all neurosurgeons.Here,we present an asymptomatic case of giant skull metastases from ICC treated with complete re-section and chemotherapy.