The role of morphine in regulation of cancer cell growth

Morphine is considered the “gold standard” for relieving pain and is currently one of the most effective drugs available clinically for the management of severe pain associated with cancer. In addition to its use in the treatment of pain, morphine appears to be important in the regulation of neoplastic tissue. Although morphine acts directly on the central nervous system to relieve pain, its activities on peripheral tissues are responsible for many of the secondary complications. Therefore, understanding the impact, other than pain control, of morphine on cancer treatment is extremely important. The effect of morphine on tumor growth is still contradictory, as both growth-promoting and growth-inhibiting effects have been observed. Accumulating evidence suggests that morphine can affect proliferation and migration of tumor cells as well as angiogenesis. Various signaling pathways have been suggested to be involved in these extra-analgesic effects of morphine. Suppression of immune system by morphine is an additional complication. This review provides an update on the influence of morphine on the growth and migration potential of tumor cells

Effects of chronic morphine treatment on tumor angiogenesis and growth.

University of Minnesota Ph.D. dissertation. June 2009. Major: Pharmacology. Advisors: Dr. Sabita Roy, PhD. Dr. S. Ramakrishnan, PhD. 1 computer file (PDF); xiii, 199 pages.Morphine is one of the most effective analgesics commonly prescribed for the treatment of severe to moderate cancer pain. To date very little is known regarding the effect of long-term morphine treatment on tumor angiogenesis. At this time, the effect of morphine on tumor growth is contradictory and still inconclusive. As solid tumors grow, the formation of a blood supply or angiogenesis is essential. In previous studies, morphine inhibited vascular endothelial growth factor (VEGF) secretion from mice cardiomyocytes and human umbilical vein endothelial cells. VEGF is a highly potent pro-angiogeneic molecule and we therefore hypothesized morphine would also inhibit angiogenesis associated with tumor growth. In the first part of these studies we show that morphine inhibited the hypoxia-induced tumor cell expression of VEGF to significantly reduce tumor cell angiogenesis, and suppress tumor growth in vivo. Additional investigations supported the view that the effect of morphine was not due to a direct effect on tumor cell apoptosis, but instead indirectly through angiogenesis. Tumor, stromal and inflammatory cells within the tumor microenvironment all contribute to a large pool of chemoattractants that increase the recruitment of myeloid cells from peripheral blood circulation into the tumor tissues. These cells mature and differentiate into neutrophils, and macrophages that eventually result in a pro-inflammatory-like environment to support and maintain tumor growth. Considering that morphine is highly immuno-suppressive, we also hypothesized that morphine will inhibit immune cell recruitment and thus angiogenesis. In an in vivo model of cell migration and recruitment we found that morphine inhibited not only CD11b+ progenitors of inflammatory cells but also the recruitment of Tie2+/CD14+ endothelial cell precursors known to actively participate in vessel formation to tumor sites. These studies have allowed us to further understand the effects of a potent analgesic such as morphine in cancer growth. Our data support the use of morphine for pain associated with cancer. Our results support the view that morphine may not cause any further detriment in the cancer patients' quality of life but further suppress angiogenesis associated with tumor growth and progression

Morphine and Immunosuppression in the Context of Tumor Growth and Metastasis

Morphine has been recognized as a highly potent analgesic agent used in cancer and non-cancer (neuropathic, surgical) pain management. Cancer patients may be prescribed morphine at different stages of the disease, during neoplastic growth and progression, during surgical resection and even in end stage palliative care. Morphine has been shown to suppress immune cell activation, ­functionality and cytokine secretion. While the initial infiltration of immune cells during tumor growth can be beneficial in destroying stressed tumor cells, ­prolonged accumulation results in a dampened immune response, enhanced angiogenesis, tumor growth and thus metastasis. The aim of this chapter is summarize the ­immunosuppressive effects of morphine as it relates to metastasis. We describe the effects of morphine as it pertains to tumor cell proliferation and growth, immune cell contribution to angiogenesis and extracellular matrix remodeling within the tumor microenvironment

Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice

Tumor cells secrete factors that stimulate the migration of peripheral blood leukocytes and enhance tumor progression by affecting angiogenesis. In these studies, we investigated the effect of morphine, a known immunosuppressant, on leukocyte migration and recruitment to conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells. Our results indicate that morphine treatment reduced the migration and recruitment of tumor-infiltrating leukocytes into Matrigel plugs and polyvinyl alcohol sponges containing conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells when compared with placebo. A reciprocal increase in peripheral blood leukocytes was observed at the time of plug or sponge removal in morphine-treated mice. Decreased angiogenesis was observed in conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells Matrigel plugs taken from morphine-treated wild-type mice when compared with placebo but was abolished in morphine-treated μ-opioid receptor knockout mice. In addition, in vitro studies using trans-well and electric cell substrate impedance sensing system studies reveal for the first time morphine's inhibitory effects on leukocyte migration and their ability to transmigrate across an activated endothelial monolayer. Taken together, these studies indicate that morphine treatment can potentially decrease leukocyte transendothelial migration and reduce angiogenesis associated with tumor growth. The use of morphine for cancer pain management may be beneficial through its effects on angiogenesis

Origin of endothelial progenitors in human postnatal bone marrow

This study demonstrates that a CD34(-), vascular endothelial cadherin(-) (VE-cadherin(-)), AC133(+), and fetal liver kinase(+) (Flk1(+)) multipotent adult progenitor cell (MAPC) that copurifies with mesenchymal stem cells from postnatal human bone marrow (BM) is a progenitor for angioblasts. In vitro, MAPCs cultured with VEGF differentiate into CD34(+), VE-cadherin(+), Flk1(+) cells - a phenotype that would be expected for angioblasts. They subsequently differentiate into cells that express endothelial markers, function in vitro as mature endothelial cells, and contribute to neoangiogenesis in vivo during tumor angiogenesis and wound healing. This in vitro model of preangioblast-to-endothelium differentiation should prove very useful in studying commitment to the angioblast and beyond. In vivo, MAPCs can differentiate in response to local cues into endothelial cells that contribute to neoangiogenesis in tumors. Because MAPCs can be expanded in culture without obvious senescence for more than 80 population doublings, they may be an important source of endothelial cells for cellular pro- or anti-angiogenic therapies.status: publishe

Rodents Versus Pig Model for Assessing the Performance of Serotype Chimeric Ad5/3 Oncolytic Adenoviruses

Oncolytic adenoviruses (Ad) are promising tools for cancer therapeutics. Most Ad-based therapies utilize species C serotypes, with Adenovirus type 5 (Ad5) most commonly employed. Prior clinical trials demonstrated low efficiency of oncolytic Ad5 vectors, mainly due to the absence of Ad5 primary receptor (Coxsackie and Adenovirus Receptor, CAR) on cancer cells. Engineering serotype chimeric vectors (Ad5/3) to utilize Adenovirus type 3 (Ad3) receptors has greatly improved their oncolytic potential. Clinical translation of these infectivity-enhanced vectors has been challenging due to a lack of replication permissive animal models. In this study, we explored pigs as a model to study the performance of fiber-modified Ad5/3 chimeric vectors. As a control, the Ad5 fiber-unmodified virus was used. We analyzed binding, gene transfer, replication, and cytolytic ability of Ad5 and Ad5/3 in various non-human cell lines (murine, hamster, canine, porcine). Among all tested cell lines only porcine cells supported active binding and replication of Ad5/3. Syrian hamster cells supported Ad5 replication but showed no evidence of productive viral replication after infection with Ad5/3 vectors. Transduction and replication ability of Ad5/3 in porcine cells outperformed Ad5, a phenomenon often observed in human cancer cell lines. Replication of Ad5 and Ad5/3 was subsequently evaluated in vivo in immunocompetent pigs. Quantitative PCR analyses 7 days post infection revealed Ad5 and Ad5/3 DNA and replication-dependent luciferase activity in the swine lungs and spleen indicating active replication in these tissues. These studies demonstrated the flaws in using Syrian hamsters for testing serotype chimeric Ad5/3 vectors. This is the first report to validate the pig as a valuable model for preclinical testing of oncolytic adenoviruses utilizing Adenovirus type 3 receptors. We hope that these data will help to foster the clinical translation of oncolytic adenoviruses including those with Ad3 retargeted tropism