Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Throughout the last decades, new developments in cellular and molecular immunology have led to a better insight in the biological nature of MM. Ever since, MM has also been regarded as a tool for studying basic concepts of the terminal B cell differentiation. The first aim of our research work, was to clarify the intraclonal maturation of the tumor clone by examining the existence of myeloma precursor cells at the genetic level. We found that myeloma patients have monoclonal B cells in the peripheral blood and bone marrow which are more immature as the malignant plasma cells and have passed through the stage of antigen selection in the germinal centre. The detection of these myeloma-related cells in the circulation implicates that these cells must be equipped with the appropriate surface receptors that allow transendothelial migration. Once entered in the marrow compartment, the myeloma cells anchor to the stromal environment where they receive the appropriate signals to proliferate and differentiate. We demonstrated that the bone marrow plasma cells express several adhesion molecules that have the potential to interact with stromal elements. We found that myeloma cell lines can bind to fibronectin (FN) and moreover are able to produce FN themselves. Functional assays revealed that FN plays only a minor role in myeloma cell binding to intact stroma, indicating the existence of other and/or multiple adhesive mechanisms. The growth of myeloma cells in the marrow compartment is not only dependent on adhesive interactions but also included the action of locally produced soluble factors. Although IL-6 has been identified as the major growth factor of myeloma cells, maintenance of tumor growth in vivo depends on one or more additional stroma-derived factors. We could establish a unique human myeloma cell line (MM5.1) that grows only in the presence of cultured human bone marrow stroma or stromal conditioned medium and not when cultured with exogeneous IL-6 alone. More recently a stroma-independent variant (MM5.2) of this line was obtained. We found that the growth of MM5.1 cells is mediated by signaling via the gp-130 transducer chain and involves IL-6 acting with a cofactor. The nature of this stromal cofactor is currently under investigation. Both variants of the cell line are also used to study differential expression of genes that are involved in clonal progression towards stroma-independency and extramedullary growth, as can be observed in patients with end stage disease.
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PMID:Homing mechanisms in the biology of multiple myeloma. 980 79

Vascular endothelial growth factor (VEGF) is the key molecule mediating tumor growth and malignant ascites formation. We recently reported that, in an end stage OVCAR-3 xenograft model, albendazole (ABZ) suppresses ascites formation, but not tumor growth. Hence, in the present study, we assessed the effect of ABZ on in vitro OVCAR-3 cell proliferation plus in vivo tumor growth, however, initiating ABZ treatment at mid stage (3 weeks post cell inoculation) rather than end stage disease. Here, ABZ treatment led to potent inhibition of cell proliferation, VEGF suppression, complete inhibition of ascites formation and most strikingly arrest of tumor growth.
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PMID:Inhibition of cell proliferation, vascular endothelial growth factor and tumor growth by albendazole. 1923 89

We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity.
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PMID:Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. 2241 55

OBJECT Despite recent advances, metastatic melanoma remains a terminal disease, in which life-threatening brain metastasis occurs in approximately half of patients. Sorafenib is a multikinase inhibitor that induces apoptosis of melanoma cells in vitro. However, systemic administration has been ineffective because adequate tissue concentrations cannot be achieved. This study investigated if convection-enhanced delivery (CED) of sorafenib would enhance tumor control and survival via inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway in a murine model of metastatic brain melanoma. METHODS Melanoma cells treated with sorafenib in vitro were examined for signaling and survival changes. The effect of sorafenib given by CED was assessed by bioluminescent imaging and animal survival. RESULTS The results showed that sorafenib induced cell death in the 4 established melanoma cell lines and in 1 primary cultured melanoma cell line. Sorafenib inhibited Stat3 phosphorylation in HTB65, WYC1, and B16 cells. Accordingly, sorafenib treatment also decreased expression of Mcl-1 mRNA in melanoma cell lines. Because sorafenib targets multiple pathways, the present study demonstrated the contribution of the Stat3 pathway by showing that mouse embryonic fibroblast (MEF) Stat3 +/+ cells were significantly more sensitive to sorafenib than MEF Stat3 -/- cells. In the murine model of melanoma brain metastasis used in this study, CED of sorafenib increased survival by 150% in the treatment group compared with animals receiving the vehicle control (p < 0.01). CED of sorafenib also significantly abrogated tumor growth. CONCLUSIONS The data from this study indicate that local delivery of sorafenib effectively controls brain melanoma. These findings validate further investigation of the use of CED to distribute molecularly targeted agents.
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PMID:Convection-enhanced delivery of sorafenib and suppression of tumor progression in a murine model of brain melanoma through the inhibition of signal transducer and activator of transcription 3. 2654 79

The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2-Stat5 signaling was assessed in vivo in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2-Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2-Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development.
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PMID:Enzalutamide-Induced Feed-Forward Signaling Loop Promotes Therapy-Resistant Prostate Cancer Growth Providing an Exploitable Molecular Target for Jak2 Inhibitors. 3154 94