Biomedical subjects

Kenneth Shain

Publications and source records attributed to Kenneth Shain.

4 recordsLinked to original sources

PubMed2005

Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects.

Infiltration of immune effector cells in tumors is critical for antitumor immune responses. However, what regulates immune cell infiltration of tumors remains to be identified. Stat3 is constitutively activated with high frequency in diverse cancers, promoting tumor cell growth and survival. Blocking Stat3 signaling in tumors in vivo results in tumor growth inhibition that involves killing of nontransfected tumor cells and infiltration of immune effector cells, suggesting that Stat3 activity in tumor cells might affect immune cell recruitment. However, dying tumor cells can also attract immune cells. In this study, we show in isogenic murine melanomas that natural Stat3 activity is associated with tumor growth and reduction of T cell infiltration. Blocking Stat3 signaling in the melanoma cells containing high Stat3 activity results in expression of multiple chemoattractants, leading to increased migration of lymphocytes, NK cells, neutrophils, and macrophages. In addition, blocking Stat3 triggers tumor cells to produce soluble factors capable of activating macrophage production of NO in vitro and in vivo. TNF-alpha and IFN-beta, which are secreted by Stat3-inhibited tumor cells, are able to activate macrophage NO production, whereas neutralizing TNF-alpha in the tumor supernatant from Stat3-blocked tumor cells abrogates nitrite production. Moreover, interrupting Stat3 signaling in tumor cells leads to macrophage-mediated, nitrite-dependent cytostatic activity against nontransduced tumor cells. These results suggest that tumor Stat3 activity affects recruitment of diverse immune effectors and it can be manipulated to activate the effector phase of innate immune responses.

Animals↗

PubMed2004

Targeting the bone marrow microenvironment in hematologic malignancies.

Unicellular drug-resistant models have been critical in elucidating intrinsic drug-resistant mechanisms; however, these models do not consider resistance mechanisms that may be elicited by extrinsic influences such as the tumor microenvironment. We propose that specific niches within the tumor microenvironment may provide a sanctuary for subpopulations of tumor cells to evade or circumvent drug-induced death and that this may represent a form of de novo drug resistance. We have found that elements of the bone marrow microenvironment, including extracellular matrices and normal stromal elements, protect malignant cells, including leukemia and myeloma cells, from drug-induced cell death. This extrinsic form of drug resistance may allow cells to survive initial drug treatment and thereby acquire a more complex, intrinsic drug-resistant phenotype. Focusing on this form of de novo drug resistance may ultimately prevent the emergence of acquired drug resistance and enhance drug therapy for hematologic malignancies.

Antineoplastic Agents↗

PubMed2003

Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells.

Although tumor progression involves processes such as tissue invasion that can activate inflammatory responses, the immune system largely ignores or tolerates disseminated cancers. The mechanisms that block initiation of immune responses during cancer development are poorly understood. We report here that constitutive activation of Stat-3, a common oncogenic signaling pathway, suppresses tumor expression of proinflammatory mediators. Blocking Stat-3 in tumor cells increases expression of proinflammatory cytokines and chemokines that activate innate immunity and dendritic cells, leading to tumor-specific T-cell responses. In addition, constitutive Stat-3 activity induces production of pleiotropic factors that inhibit dendritic cell functional maturation. Tumor-derived factors inhibit dendritic cell maturation through Stat-3 activation in progenitor cells. Thus, inhibition of antitumor immunity involves a cascade of Stat-3 activation propagating from tumor to dendritic cells. We propose that tumor Stat-3 activity can mediate immune evasion by blocking both the production and sensing of inflammatory signals by multiple components of the immune system.

Animals↗

PubMed2000

Multiple Myeloma: New Insights and Therapeutic Approaches.

This review discusses the evolution of novel diagnostic and treatment strategies for multiple myeloma based upon increased understanding of basic disease pathogenesis. Although myeloma has remained an incurable illness to date, these new developments will derive treatments to improve outcome and achieve eventual cure. In Section I, Dr. Kyle reviews the results of current therapy for multiple myeloma, including high dose therapy and stem cell transplantation which have proven to achieve improved response rates, event-free, and overall survival. Supportive therapy, such as erythropoietin to treat disease-related anemia, and methods of prophylaxis against infection, which both lessen toxicities of treatment and improve quality of life for patients, are also addressed. In Section II, Dr. Dalton with Drs. Landowski, Shain, Jove and Hazlehurst discusses mechanisms of drug resistance in myeloma, with emphasis on novel treatment approaches to prevent development of drug resistance and to overcome drug resistance. Laboratory studies delineating mechanisms whereby myeloma cells resist drug-induced apoptosis provide the framework for related treatment protocols for patients with refractory disease. In Section III, Dr. Berenson reviews the management of complications in bone, which occur in the majority of patients with myeloma and are the major cause of decreased quality of life. New insights into the mediators of bone resorption and new bone formation in the marrow milieu have already derived effective bisphosphonate therapy. These drugs not only reduce bone complications and related pain, thereby improving quality of life, but also may have intrinsic anti-tumor activity by virtue of inducing tumor cell adherence to marrow, reducing interleukin-6 secretion, inducing tumor cell apoptosis, or inhibiting angiogenesis. In the last section, Dr. Anderson explores the potential for future therapies which offer great promise to improve patient outcomes. First, drugs which alter the marrow microenvironment include thalidomide and its derivative immunomodulatory drugs, which act directly on tumor cells to induce apoptosis or G1 growth arrest, alter tumor cell adhesion to marrow stroma, inhibit angiogenesis, and trigger a cellular anti-tumor response. The proteasome inhibitors both act directly on tumor cells and also inhibit the transcription factor NFkappaB-dependent upregulation of IL-6 secretion triggered by tumor cell adhesion. Second, delineation of both growth and apoptotic pathways has derived novel treatment strategies. Third, the preclinical basis and early clinical trial results using vaccination and adoptive immunotherapy to harness autoimmune and alloimmune anti-myeloma responses are presented. This review sets the stage for an evolving new biologically based treatment paradigm in myeloma targeting both the tumor and its microenvironment to improve outcome and achieve eventual cure.

Journal Article↗