Gil Ziv, MD PhD
Associate Professor of Medicine
MD, 2001 - Ben Gurion University, Israel
PhD, 2000 - Ben Gurion University, Israel
Tumor invasion and chemoresistance
A ‘‘tumor’’ is more than a homogenous population of cancer cells, as this mass also encompasses stroma - the extracellular and cellular framework that surrounds and interacts with cancer cells. The stroma is by no means a passive bystander, it is an active participant that may foster tumor development, promote metastasis and even render cancer cells resistant to chemotherapy. The long-term research objective of my laboratory is to understand the interaction between cancer and stromal cells, with the aim of harnessing this unique knowledge towards developing novel therapies for cancer patients.
In recent years we have focused our attention on tumor-stromal communication in the pancreas and brain. We found that stromal cells, including macrophages and Schwann cells (and astrocytes in the CNS) play a pivotal role in cancerous dissemination along nerves towards the peripheral nervous systems. We identified a population of tumor-associated macrophages that dominate the peri-neural niche and secrete a ligand known as GDNF (Glial Derived Growth Factor). In turn, GDNF stimulates RET thyrosine kinase receptors on tumor cells, stimulating them to invade into the nerves. Expanding on the role of tumor-associated macrophages, we recently demonstrated that macrophages cause chemotherapy resistance, by enabling inactivation of the drug inside the cancer cell. The macrophage-cancer cell communication was found to be mediated by exosomes – nano spheres that shuttle miRNAs between the cells.
Shabtay-Orbach A, Amit M, Binenbaum Y, Na’ara S, and Gil Z. 2015. Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial-derived neurotrophic factor. International Journal of Cancer 137, 1012-20.
Weizman N, Krelin Y, Shabtay-Orbach A, Amit M, Binenbaum Y, Wong RJ, and Gil Z. 2014. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 33, 3812–9.
Krelin Y, Berkovich L, Amit M, and Gil Z. 2013. Association between tumorigenic potential and the fate of cancer cells in a syngeneic melanoma model. PloS One 8, e62124.
Cavel O, Shomron O, Shabtay A, Vital J, Trejo-Leider L, Weizman N, … Gil Z. 2012. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Research 72, 5733–43.
Gil Z, Cavel O, Kelly K, Brader P, Rein A, Gao SP, … Wong RJ. 2010. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. Journal of the National Cancer Institute 102, 107–18.
microRNA shuttling between cancer and stromal cells.
(A) Exosomes secreted by tumor-associated macrophages (labeled green) were incubated with pancreatic cancer cells. 75 minutes post incubation, cells were imaged using confocal microscopy. The figure shows exosomes are internalized to the cancer cell.
(B) Imaris-cell analysis of exosome distribution in the host pancreatic cancer cell. The green signals were denoted as spheres, with the sphere color (red or blue) indicating distance from the plasma membrane or nucleus membrane, respectively.
(C) The graph is a quantitative representation of (B). It is evident that most exosomes accumulate near the plasma membrane, while a small fraction enters the nucleus of the cancer cell.
(D) Schematic model for macrophage-induced chemotherapy resistance. Tumor associated macrophages secrete miRNA rich exosomes. Exosomes are internalized to the cancer cell, facilitating inactivation of the chemotherapy.