Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sentinel lymph node (SN) is the first node on the direct lymphatic drainage pathway from a tumor. Melanoma-associated SNs are the most likely site of early metastases and their immune functions are strikingly down-modulated. We evaluated histologic and cytologic characteristics of 21 SNs and 21 nonsentinel nodes (NSNs) from melanoma patients who had clinically localized (AJCC Stage I--II) primary cutaneous melanoma. SNs showed highly significant reductions in total paracortical area and in the area of the paracortical subsector occupied by dendritic cells. The frequency of paracortical interdigitating dendritic cells (IDCs) was dramatically reduced in SNs, and most IDCs (approximately 99%) lacked the complex dendrites associated with active antigen presentation. The release of immunosuppressive factors from the primary melanoma may induce a localized and specific paralysis in the SN, which prevents the recognition of otherwise immunogenic melanoma antigens by IDCs. This immune paralysis may facilitate the implantation and growth of melanoma cells in the SN. Cytokine therapy may be able to reverse this immune paralysis. These findings have an important practical application in the histopathologic confirmation that a node is truly sentinel. They also offer an hypothesis to explain the failure of the immune surveillance mechanisms to identify and respond to a small primary melanoma that expresses immunogenic tumor antigens.
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PMID:Sentinel lymph nodes show profound downregulation of antigen-presenting cells of the paracortex: implications for tumor biology and treatment. 1140 63

To examine tolerability and activity of local, intratumoral tumor necrosis factor-alpha (TNF-alpha) and systemic interferon-alpha2b (IFN-alpha2b) in locally advanced, hormone-resistant prostate cancer (LA-HRPC), 10 patients with LA-HRPC (T4N x M0, n = 3, T4N x M1, n = 5; T4N1M1, n = 2) were treated with recombinant TNF-alpha injected locally into prostate tumor tissue at 4-week intervals (maximum of four cycles) combined with intermittent subcutaneous (s.c.) administration of 5 x 10(6) IU IFN-alpha2b. Twenty-nine TNF-alpha cycles were administered. Despite significant TNF-alpha leakage into the systemic circulation 2 h after intraprostatic application (from a mean of 9 to a mean of 416 pg/ml; p = 0.0034), TNF-alpha (and IFN-alpha2b) was well tolerated (WHO grade 1-2 toxicity), possibly because of its rapid neutralization by increasing soluble 55-kDa and 75-kDa TNF receptor levels in the serum (mean increase 268% and 91%, respectively) at the same time. TNF-alpha induced prostate tumor cell necrosis in all patients, leading to a significant reduction of prostate volume in 9 of 10 cases (mean 38%; p = 0.0025). The significant short-term increase of prostate-specific antigen (PSA) (mean 65%; p < 0.001), tissue polypeptide-specific antigen (TPS) (mean 85%; p = 0.001), and possibly interleukin-8 (IL-8) (mean 2687%; p < 0.009) serum levels within 4 h after TNF-alpha confirmed the cytotoxic effect in vivo. In the long term, serum PSA levels dropped by 18%-87%, reaching the nadir value 7 weeks after baseline. Objective responses of metastases were not seen. Intraprostatic administration of TNF-alpha is feasible at a tolerable toxicity in patients with LA-HRPC and, thus, may be a new treatment option for these patients.
J Interferon Cytokine Res 2001 Jul
PMID:Local intratumoral tumor necrosis factor-alpha and systemic IFN-alpha 2b in patients with locally advanced prostate cancer. 1150 41

The development of cancer cachexia has been linked to cytokines related to interleukin6 (IL-6). We examined the kinetics of IL-6, IL-11, oncostatinM (OSM) and leukaemia inhibitory factor (LIF) induction in the splenocytes of tumour-bearing mice. Using a lung carcinoma line, which grows in C57BL/6J mice, we observed that when the tumour grew and cachexia was observed, the splenocytes produced IL-6, IL-11, and OSM, but not LIF. Cytokine expression was observed within 1 week (day 3 for IL-6 and IL-11, and day 1 for OSM) of administration of tumour cells, and was observed in splenocytes without tumour metastases to the spleen. Cytokine expression preceded cachexia (determined by changes in serum triglyceride levels and decrease in epididymal fat-pad weights) development by over 1 week. Exogenous administration of IL-11 resulted in the accelerated onset of cachexia, compared to control protein treatment, but without an effect on the tumour burden. In vivo treatment with a neutralizing dose of anti-OSM antibody inhibited the triglyceride dysregulation only until the synthesis of IL-6 and IL-11 began in the spleen (day 3). Afterward, IL-6 and IL-11 induced lipid catabolism in the absence of functional OSM. We conclude from the data described above that cachexia developed due to a systemic cytokine response induced by a tumour burden, and that IL-6-like cytokines contributed independently to lipid hypercatabolism in the aetiology of cancer cachexia.
Cytokine 2001 Dec 21
PMID:Cancer cachexia is mediated in part by the induction of IL-6-like cytokines from the spleen. 1188 29

We have reviewed the experimental results which indicate that endogenous type I interferon (IFN) present either constitutively or possibly induced by the tumor plays an important role in limiting the development of transplantable tumors in mice. Thus, treatment with potent polyclonal neutralizing antibodies to IFN alpha/beta markedly enhanced the subcutaneous growth, invasiveness and metastases of xenogeneic tumor cells (uninfected or infected with RNA or DNA viruses) in athymic nude mice; enhanced the intraperitoneal transplantability of six different syngeneic murine tumors in three strains of immunocompetent mice; and completely abrogated the resistance of allogeneic C57Bl/6 (H-2(b)) or C3H (H-2(k)) mice to the multiplication of Friend erythroleukemia cells (H-2(d)) in the liver and spleen resulting in the death of most mice. The mechanisms by which mice respond to the injection of relatively few tumor cells appear to be multiple, to depend on the site of tumor growth, to occur early and prior to an immunologic response. Endogenous type I IFN appears to constitute an essential component of these defense mechanisms enabling the host to restrict tumor growth.
Cytokine Growth Factor Rev 2002 Apr
PMID:Endogenous type I interferons as a defense against tumors. 1190 Sep 87

HER-2/neu peptides have recently been shown to induce a proliferative response by peripheral CD4(+) T cells in breast cancer patients. To investigate potential differences in the local cellular immune response between breast cancer patients with and without nodal metastases, lymphocytes were isolated from axillary lymph nodes from patients with breast cancer, and proliferative and cytokine responses to HER-2/neu peptides were determined. Freshly isolated lymphocytes from lymph nodes of 7 women undergoing surgery for invasive breast cancer were plated at 20 x 10(5) cells per well in triplicate. Cells were stimulated with HER-2/neu peptides at 50 microg/ml and with control antigens. Incorporation of tritium-labeled thymidine was determined 4 days later. The levels of the cytokines interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and IL-10 were determined at priming and at restimulation with HER-2/neu peptides using a cytokine-specific, double-sandwich, enzyme-linked immunosorbent assay (ELISA). Lymphocytes isolated from the axillary lymph nodes of the patients mounted significant cellular immune response to HER-2/neu peptides, manifested by proliferation and specific cytokine elaboration. Proliferative responses to HER-2/neu peptides were seen in lymphocytes of patients with and without overexpression of HER-2/neu in the primary tumor. In some patients, the proliferative response to HER-2/neu peptides in lymphocytes from lymph nodes with metastases was absent or blunted compared with the response in lymphocytes from lymph nodes without metastases from the same patient (p < 0.05). HER-2/neu peptides induced a predominantly T helper type 1 (Th1) pattern of cytokine response in nodal lymphocytes isolated from breast cancer patients. A Th1-specific cytokine production pattern was maintained at priming and restimulation with HER-2/neu peptides and was amplified with IL-12 costimulation. These results indicate that HER-2/neu peptides can activate T cells in draining lymph nodes from women with invasive breast cancer. This activation is associated with a predominantly Th1 cytokine response, which suggests that conditioning with HER-2/neu peptides may be of value in the development of breast cancer vaccines.
J Interferon Cytokine Res 2002 May
PMID:Axillary lymph node cellular immune response to HER-2/neu peptides in patients with carcinoma of the breast. 1206 Apr 97

The immunological dysfunction associated with human cancer is well known phenomenon. It comprises number of pathological changes within immune network including imbalance in cytokines of Th1/Th2 origin. The objectives of our study were (i) to evaluate the abnormalities in serum levels of selected cytokines in malignant melanoma patients with regional lymph node metastases as compared to normal values, (ii) to examine the relationship between postoperative cytokine levels and disease progression and (iii) to correlate cytokine profile changes during IFN-alpha therapy with the disease progression and potential therapeutical response. Nine Th1/Th2 related cytokines and sIL-2R were determined in 26 malignant melanoma patients at clinical stage III prior and during adjuvant immunotherapy. Control group consisted of 26 healthy persons. Patients were treated with rIFN-alpha according to EORTC Melanoma group protocol 18952. Cytokines were quantified in patients sera using commercial ELISA kits. Majority of melanoma patients showed significantly lower values of IL-2 and IFN-gamma and pathologically elevated levels of IL-4, IL-6, IL-10 as compared to healthy subjects what indicates disease associated Th1/Th2 imbalance. In addition increased IL-12 and IL-15 values were noted in some patients (54% and 27%, respectively). All patients who manifested early relapse during immunotherapy had significantly lower pretreatment levels of IL-2 and IL-12 than those remaining without progression and probably benefiting from the treatment. Cytokine changes during immunotherapy disclosed that decreases in IL-2 and IL-12 and raises in IL-6 and IL-10 values occurred at least one month prior to relapse. Moreover, the continuous elevation of TNF-alpha and sIL-2R could be observed in patients who remained without progression during 10 months lasting immunotherapy. Our data illustrate that malignant melanoma associates with Th1/Th2 perturbances which are directed towards extended Th2 responses and that measurement of selected cytokines of Th1/Th2 category may be used as an early signal of disease deterioration and for evaluation of immunotherapy response.
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PMID:Malignant melanoma associates with Th1/Th2 imbalance that coincides with disease progression and immunotherapy response. 1209 1

Cytokine therapy for patients with metastatic renal cancer is based on observations suggesting this neoplasm may be responsive to immunotherapy. Two cytokines, interferon-alpha (IFN-alpha) and interleukin 2 (IL-2) induce tumor regression in 10% to 15% of patients with metastatic disease. Randomized trials demonstrate a modest survival advantage for patients treated with IFN-alpha, as compared with chemotherapy. The combination of IL-2 and IFN-alpha appears to be associated with improved response rates, but has no demonstrable effect on survival. The addition of other cytokines (e.g., GM-CSF) or chemotherapy to this combination has been investigated, but results do not suggest that they enhance the outcome. Patient selection remains an important issue in this patient population. Individuals who are asymptomatic and have limited pulmonary or soft-tissue disease are most likely to benefit. The addition of novel cytostatic agents to these regimens is now under way.
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PMID:[Cytokine therapy for metastatic renal cell carcinoma]. 1240 23

Mice deficient for the STAT6 gene (STAT6(-/-) mice) have enhanced immunosurveillance against primary and metastatic tumors. Because STAT6 is a downstream effector of the IL-4R, and IL-13 binds to the type 2 IL-4R, IL-13 has been proposed as an inhibitor that blocks differentiation of tumor-specific CD8(+) T cells. Immunity in STAT6(-/-) mice is unusually effective in that 45-80% of STAT6(-/-) mice with established, spontaneous metastatic 4T1 mammary carcinoma, whose primary tumors are surgically excised, survive indefinitely, as compared with <10% of STAT(+/+) (BALB/c) mice. Surprisingly, STAT6(-/-) and BALB/c reciprocal bone marrow chimeras do not have increased immunosurveillance, demonstrating that immunity requires STAT6(-/-) hemopoietic and nonhemopoietic components. Likewise, CD1(-/-) mice that are NKT deficient and therefore IL-13 deficient also have heightened tumor immunity. However, STAT6(-/-) and CD1(-/-) reciprocal bone marrow chimeras do not have increased survival, suggesting that immunity in STAT6(-/-) and CD1(-/-) mice is via noncomplementing mechanisms. Metastatic disease is not reduced in BALB/c mice treated with an IL-13 inhibitor, indicating that IL-13 alone is insufficient for negative regulation of 4T1 immunity. Likewise, in vivo depletion of CD4(+)CD25(+) T cells in BALB/c mice does not increase survival, demonstrating that CD4(+)CD25(+) cells do not regulate immunity. Cytokine production and tumor challenges into STAT6(-/-)IFN-gamma(-/-) mice indicate that IFN-gamma is essential for immunity. Therefore, immunosurveillance in STAT6(-/-) mice facilitates survival against metastatic cancer via an IFN-gamma-dependent mechanism involving hemopoietic and nonhemopoietic derived cells, and is not exclusively dependent on counteracting IL-13 or CD4(+)CD25(+) T cells.
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PMID:Resistance to metastatic disease in STAT6-deficient mice requires hemopoietic and nonhemopoietic cells and is IFN-gamma dependent. 1242 60

All of these studies taken together highlight key areas that must be addressed in the future in order for the field to continue to move forward. These issues are many, including but not limited to method of delivery of dendritic cells to patients, maturation status of the dendritic cells, and methods of monitoring responses to these vaccines. Each of these requires some comment. Different strategies of immunization were used in these studies. DCs were injected at various times and in various locations, including intradermally/subcutaneously, intranodally, and intravenously. Investigation of the pattern of spread of subcutaneously injected fluorescently labeled DCs in the chimpanzee was studied at the University of Pittsburgh. Although rodent DCs had previously been shown to remain at the site of injection, these immature primate DCs migrated to draining lymph nodes and interact appropriately with T cells for as long as 5 days after administration. Data not shown in the same study reveal that intravenously administered DCs were undetectable in draining lymph nodes. Two groups have undertaken evaluation of route of administration of DCs in humans. The first of these examined migration of immature, indium-111-labeled dendritic cells after RNA-loading in metastatic cancer patients [44]. The DCs were injected either intravenously, subcutaneously, and intradermally. Only DCs injected intradermally were cleared from the injection site with migration to regional lymph nodes. The immunologic significance of these findings is unclear, however. Another study examined this issue by studying prostatic acid phosphatase (PAP) protein-loaded mature DCs injected intravenously, intradermally, and intralymphatically in prostate cancer patients [45]. Regardless of route of administration, T cell responses were induced as measured by proliferation when PBMCs in vitro were stimulated with the PAP protein. Cytokine analysis of the patients revealed that the majority of patients undergoing either intralymphatic or intradermal injection had increases in measurable interferon-gamma but that none of the intravenously-injected patients did. The intralymphatic and intradermal routes thus seem to lead to stronger Th1 responses. But no data was presented regarding the numbers of PAP precursors induced by vaccination nor their specificity/cytotoxicity. Another issue in DC administration that should also affect route of administration is maturation status of the dendritic cells. Many of the studies used immature dendritic cells to immunize patients whereas others used mature cells. A number of studies have demonstrated that maturation signals such as inflammatory cytokines and CD40 ligation lead to down-regulation of antigen processing and up-regulation of the chemokine receptor CCR7, which leads to homing to lymph nodes [46] as well as the MHC molecules, costimulatory molecules, and maturation markers [8,47,48]. In addition, different maturation agents and sequences of addition of these maturation agents may lead to differences in functions of dendritic cells [48-51]. Others have found that injection of immature DCs pulsed with influenza matrix peptide and KLH, and lead to greater numbers of influenza-specific T cells, but these cells had reduced interferon-gamma production and lacked killer activity [52]. Perhaps the most impressive results in a clinical trial, however, were gained by injecting similar cells loaded with melanoma peptides [21]. In addition, sequence of loading and maturation may be important in creating vaccines. One study using CEA peptides and CEA RNA found that optimal T cell presentation occurs when peptides are loaded after maturation with CD40 ligand and when RNA is transfected before maturation with CD40 ligand [53]. As all of these studies reveal, more investigation into the role of DC maturation as well as its timing and sequence is needed. Finally, a multitude of methods to detect response to vaccination have been attempted in all of the above studies. Many use DTH responses, but these may measure CD4 T cells instead of CD8 T cells. The availability of tetramers allows easier quantification of CTL precursors, but they provide no assessment of the function of these T cells. Enzyme-linked immunospot assays allow identification and quantification of numbers of cells producing cytokines such as interferon-gamma when encountering target antigens, but cytokine production may not correlate with tumor cell killing. Chromium release assays or flow cytometric assays for molecules such as perforin may be used to validate killing, but inability of many tumors to grow in vitro precludes direct assessment of tumor cell killing via this method. Other responses in human subjects may also be measured. Some of the cited studies yielded clinical responses that could be measured via physical examination or radiologic study. This is the exception rather than the rule, however. Others have monitored the decrease in serum tumor markers such as PSA or CEA. But these may not correlate directly with tumor burden. Indirect calculation of tumor burden by using quantitative PCR to estimate the number of circulating tumor cells in peripheral blood may be promising in this regard. Despite the lack of consensus as to what constitutes an effective response, most would agree that monitoring of these patients should include measures of both immunologic response and clinical tumor effect. All of this leads to the conclusion that DC-based cancer vaccines have progressed a great deal but that much work still needs to be done. Only rigorous bench top experimentation followed by careful patient selection and vaccine administration, and then by meticulous patient monitoring, will lead to advances in the field.
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PMID:Dendritic cell gene therapy. 1248 60

As the TNF and TNFR superfamilies have grown to more than two dozen combined members over the past 30 years, their involvement in interactions between immune cells, with regard to the events governing cellular differentiation, activation, and survival have been well established. The recently identified TNF superfamily cytokine, TRANCE (RANKL/OPGL/ODF/TNFSF11), which interacts with two receptors-one functional, TRANCE-R (RANK/TNFRSF11A), and one decoy, OPG (TNFRSF11B)-is a survival factor for activated dendritic cells, and may also be important for the maintenance of immune tolerance. TRANCE is also the key cytokine involved in osteoclast differentiation and activation, making TRANCE signaling crucial for proper bone homeostasis, and a potential therapeutic target in diseases such as osteoporosis, osteolytic metastatic cancer, arthritis, and periodontitis. Importantly, the positive role that TRANCE has in activating the immune system, appears to significantly contribute to pathologic bone loss. These observations have spurred intense study of the various ways in which the immune system can influence bone. Furthermore, TRANCE has also been demonstrated to play essential roles in the developmental processes leading to both lymph node formation, and the expansion and function of mammary glands during pregnancy and lactation. Thus, TRANCE is quickly emerging as a cytokine of significant importance to further understanding unique aspects of mammalian biology.
Cytokine Growth Factor Rev
PMID:Biology of the TRANCE axis. 1278 63


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