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Signaling and Microenvironment
By Dharminder Chauhan, Ph.D., Dana Farber Cancer Institute
07.14.01

INTRODUCTION

Most anticancer drugs kill cancer cells through a process called programmed cell death, or apoptosis. Disruption of the apoptotic process by factors (cytokines) present in the tumor microenvironment may promote tumor initiation, progression, and treatment resistance. This session focused on identifying various signaling proteins that can be targeted for therapeutics based on their ability to either trigger apoptosis or inhibit growth/survival of tumor cells. 

HIGHLIGHTS

In myeloma, tumor cells are predominantly localized to the bone marrow microenvironment because they adhere to bone marrow cells. This interaction between tumor cells and bone marrow cells stimulates production of various cytokines, such as interleukin (IL)-6, which not only potentiate growth and survival of multiple myeloma (MM) cells but also support development of drug resistance. High serum levels of IL-6 observed in MM patients contribute to chemoresistance and treatment failure. For example, dexamethasone, a drug used in treatment of MM, kills MM cells; however, in the presence of IL-6, the effectiveness of dexamethasone is significantly reduced. Thus, the cytokines present within the bone marrow microenvironment may negatively regulate drug-induced death in MM cells. Defining the signaling pathways mediating cell death, growth, and chemoresistance in MM cells may lead to new and effective treatment strategies based on targeting growth and survival proteins.

Dr. Chauhan discussed the interactions between growth– and cell-death–signaling pathways in myeloma cells. In particular, dexamethasone-mediated myeloma cell killing requires enzymatic activation of proteins such as RAFTK (related adhesion focal tyrosine kinase), Smac (second mitochondrial activator of caspases), and caspase-9 Deleting these proteins renders cells resistant to dexamethasone; conversely, higher levels of proteins may sensitize cells to dexamethasone. Importantly, IL-6’s protective effect against dexamethasone killing also requires growth-promoting proteins, such as SHP2 (Src-homology protein tyrosine phosphatase-2). SHP2 interacts with RAFTK and stops dexamethasone-induced cell death. IL-6 also promotes activation of the growth-signaling protein MAPK (mitogen-activated protein kinase). Dexamethasone activates caspases (enzymes that execute the death signals). In contrast, IL-6 increases levels of proteins such as IAPs (inhibitors of apoptosis proteins), which block caspase functions and thereby prevent dexamethasone-induced cell death. Interestingly, higher levels of anti-cell-death proteins such as IAPs are observed in patients with advanced myeloma. New treatment strategies based on either inhibiting the survival proteins or enhancing the functionality of death proteins may improve drug efficacy.

Dr. Jernberg Wilkund of Uppsala University in Sweden discussed the roles of interferon-gamma (IFN-g) and insulin growth factor (IGF-I), which may determine the sensitivity of MM cells to dexamethasone or Fas-induced cell death. Blocking the IGF-I Receptor (IGF-IR) with anti-IGF-IR antibodies increases dexamethasone- and Fas-induced death in MM cells. Using antibodies specific to either IFN-g or IGF-IR can restore the normal cell-death pathway. IGF-IR signaling may confer resistance to apoptosis and may constitute a novel mechanism for the development of chemoresistance in MM.

Dr. Amiot of the Institut de Biologie in France discussed another growth-signaling pathway that is triggered by IL-6 via a protein called protein kinase C-delta (PKC-d). Rottlerin, a specific inhibitor of PKC-d, induces death in myeloma cells. Additional proteins that regulate the PKC pathway are PI3K/AKT and MAPK. Treatment of myeloma cells with wortmanin, a specific blocker of PI3K, stops the PKC-d-induced growth signals. Targeting PKC-d and associated proteins may therefore be useful therapeutic strategies. 

Dr. Regis Bataille, also of the Institut de Biologie, discussed IL-6 as an essential factor for the expansion/growth of MM cells within the bone marrow microenvironment. Based on these studies, numerousnew therapeutic approaches were suggested, including neutralizing the IL-6 receptor present on the MM cell surface and using anti-IL-6 antibodies. Several clinical trials are currently under way using neutralizing anti-IL-6 antibody in combination with conventional drugs such as, dexamethasone and melphalan. These studies have shown encouraging results, with remissions in advanced-stage MM patients. IL-6 also induces the anti-cell-death protein MCL-1, which may be a useful therapeutic tool to stop tumor cell growth and survival in the bone marrow.

Another mechanism whereby the bone marrow microenvironment affects myeloma cell growth was discussed by Dr. Vanderkerken of the Free University in Belgium. A distinct category of factors (chemokines) are produced by bone marrow cells, which attract MM cells and thereby facilitate homing of MM cells to the bone marrow. For example, MCP-1 (monocyte-chemoattractant protein-1) or IGF-I is secreted by bone marrow cells and binds to receptors present on myeloma cells (CCR2) and IGF-IR. Importantly, this interaction can be prevented by using specific antibodies to MCP-1 or IGF-I and thereby blocking homing of MM cells to bone marrow. Other molecules that were shown to play similar roles include MMP-9 and CD44v6.


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