Interplay between cancer cells, macrophages and natural killer cells may actually decide the outcome of therapy with sorafenib
Authors: Ciprian Tomuleasa, Gianluigi Giannelli, Andrei Cucuianu, Mihaela Aldea, Angelo Paradiso, Ioana Berindan-Neagoe
Journal: Hepatology (2013)

We read with great interest the article of Sprinzl et al.1 in Hepatology. The group highlighted the antitumoral effects of sorafenib in hepatocellular carcinoma (HCC) from an immunological point of view. Still, the “off-target” effects on the cancer microenvironment are far from clear. The tumor microenvironment is formed by a wide variety of cells that include endothelial cells, fibroblasts, tumor-associated macrophages (TAMs), natural killer (NK) cells, and malignant cells, all of which communicate with each other through a complex network of cytokines and growth factors. A consistent stromal compartment within the cancer mass has been associated with worse disease outcome and increased cancer metastasis, as it supports the cancer cell, as well as modulates the response to chemotherapy.2 TAMs are correlated with decreased survival and a higher rate of HCC recurrence because of their inhibitory effects on NK cells and T lymphocytes. But sorafenib is known to stimulate TAMs by way of mitogen-activated protein kinase (MAPK), NF-κB, and MAPKp38 pathways, thus contributing to the inhibition of a proinflammatory environment and indirectly stimulating the progression of cancer. Sprinzl et al. have proven that sorafenib also stimulates the local immune system of the malignant niche by activating NK cells by way of TAM sensitization. The macrophages go through the transition into TAM due to sorafenib's stimulation of the colony-stimulating factor receptor 1 (CSF-R1), MAPKp38, and the STAT3 pathways. Nevertheless, these data do not match perfectly with some information from other articles published in the last few years.3 We are confident that the data provided by our colleagues are important in understanding the basic mechanisms of tumor cell progression and dissemination during chemotherapy and in accordance with international literature. But sorafenib has a suppressive effect on the cancer niche by targeting the NK cell, results that suggest another conclusion in comparison with the one drawn by the article first cited in our letter.4 Zhang et al. bring compelling evidence that it acts directly on the NK cell's proliferation and function by inhibiting ERK signaling. This translates into an increased potential of the cancer to invade the surrounding healthy tissues, but also distant organs in the absence of a strong immune response. Taking into consideration all the data published recently, we suggest that further research should be carried out in the field of tumor immunology and translational immunopharmacology, as contradicting evidence can only emphasize the complexity of molecular signaling of the cancer. Ciprian Tomuleasa, M.D., Ph.D.1,2 Gianluigi Giannelli, M.D., Ph.D.3 Andrei Cucuianu, M.D., Ph.D.2 Mihaela Aldea, M.D.1 Angelo Paradiso, M.D., Ph.D.4 Ioana Berindan-Neagoe, Ph.D.1 1Center for Functional Genomics and Translational Medicine Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Romania 2Department of Hematology Ion Chiricuta Comprehensive Cancer Center Cluj Napoca, Romania 3Department of Internal Medicine Immunology and Infectious Diseases Section of Internal Medicine University of Bari Medical School Bari, Italy 4Clinical Experimental Oncology Laboratory National Cancer Institute Giovanni Paolo II Bari, Italy