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)

Adoptive cellular immunotherapy, infusions of interleukin 2 (IL-2) in conjunction with in vitro-activated killer cells, has brought new hope to patients with cancer. The broad application of this strategy, however, is constrained by the need for repeated leukapheresis and by the labor-intensive process of in vitro activation of cells. Also, current protocols generally use nonphysiological and toxic concentrations of IL-2. Identification of an in vivo stimulant that renders T cells responsive to physiologic concentrations of IL-2 represents a potential improvement over existing approaches. We have determined whether in vivo administration of monoclonal antibodies (mAbs) directed at the T-cell surface protein CD3 induces T-cell responsiveness to IL-2, stimulates cytolytic molecular programs of natural killer cells and cytotoxic T cells, and induces tumor regression. These hypotheses were explored in a murine hepatic MCA-102 fibrosarcoma model. We report that in vivo administration of anti-CD3 mAbs plus IL-2 results in intrahepatic expression of mRNA-encoding perforin, cytotoxic T-cell-specific serine esterase, and tumor necrosis factor alpha. Anti-CD3 mAbs alone or IL-2 alone failed to induce or induced minimal expression of these molecular mediators of cytotoxicity. The anti-CD3 mAbs plus IL-2 regimen also resulted in a significantly smaller number of hepatic metastases and a significantly longer survival time of tumor-bearing mice, compared to treatment with anti-CD3 mAbs alone or IL-2 alone. Our findings suggest that a regimen of anti-CD3 mAbs plus IL-2 is a more effective antitumor regimen compared with anti-CD3 mAbs alone or IL-2 alone and advance an alternative immunotherapy strategy of potential value for the treatment of cancer in humans.
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PMID:Immunotherapy with anti-CD3 monoclonal antibodies and recombinant interleukin 2: stimulation of molecular programs of cytotoxic killer cells and induction of tumor regression. 805 30

The response rate to IL-2 immunotherapy, currently used in the treatment of metastatic renal cell cancer, is limited. Based on our earlier demonstration that a combined regimen of monoclonal antibodies directed at the T cell surface protein CD3 (anti-CD3 mAbs) and IL-2 is synergistic in constraining tumor progression in a murine fibrosarcoma hepatic metastasis model, we have explored the efficacy of an anti-CD3 mAbs plus IL-2 regimen in a murine renal cell cancer model. Our studies demonstrate that a regimen of anti-CD3 mAbs plus IL-2 is superior to treatment with anti-CD3 mAbs alone or IL-2 alone in reducing the number of pulmonary metastases and in prolonging survival. Moreover, the efficacious regimen is associated with heightened intrapulmonary expression of mRNA encoding cytotoxic attack molecules (perforin, granzyme B) and immunoregulatory cytokines (IL-4, IL-10 and IFN- gamma).
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PMID:Immunostimulatory therapy with anti-CD3 monoclonal antibodies and recombinant interleukin-2: heightened in vivo expression of mRNA encoding cytotoxic attack molecules and immunoregulatory cytokines and regression of murine renal cell carcinoma. 914 77

MAGE (Melanoma antigen E) family gene products encompass tumour-associated antigens (TAAs) recognised by human leukocyte antigen (HLA)-restricted specific T-cells. Agents inducing DNA demethylation, an event typically detectable in cellular de-differentiation processes, were shown to induce the expression of MAGE genes. By using a monoclonal antibody specific for MAGE family gene products, we have studied the expression of these TAAs in a group of 144 patients with invasive ductal breast cancers. Immunohistochemical data were correlated with tumour differentiation, lymphatic vessel invasion, oestrogen receptor expression, intratumoural necrosis, lymphocytic infiltration, perineural invasion, tumour microcalcifications and axillary lymph node metastases. MAGE immunoreactivity was undetectable in non-neoplastic cells. In poorly differentiated cancers positive staining was observed in 30/63 cases (47.6%) as compared with 13/51 (25.4%) and 5/30 (16.6%) in moderately and well-differentiated tumours, respectively (P<0.05). In addition, MAGE immunoreactivity was significantly correlated with lymphatic vessel invasion and intratumoural necrosis. Moreover, a significant inverse relationship with oestrogen receptor expression was also observed. However, no significant correlation could be established between MAGE immunoreactivity and defined phenotypic characteristics of tumour infiltrating lymphocytes, including expression of CD3, CD4, CD8, CD20 or granzyme B. Thus, expression of MAGE family gene products in invasive ductal breast cancers appears to be associated with poorly differentiated histological phenotypes. These data support the concept of specific immunotherapy in highly aggressive forms of breast neoplasms. Furthermore, they suggest that MAGE immunoreactivity could represent a tumour marker of potential prognostic relevance.
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PMID:Expression of MAGE tumour-associated antigens is inversely correlated with tumour differentiation in invasive ductal breast cancers: an immunohistochemical study. 1156 52

We report here on 2 patients who received adjuvant vaccination with an HLA-A2- or HLA-A24-restricted tyrosinase peptide, respectively, and GM-CSF for frequently relapsing stage IV melanoma. Following resection of metastases and irradiation of brain metastases in 1 patient, both patients were without evidence of disease when receiving the first vaccination. While the patients had had 9 and 12, respectively, mostly s.c., relapses during the 3 years before vaccination, they experienced freedom from relapse for more than 2 years after vaccination. We found a T-cell response to the vaccine peptide in both patients in the peripheral blood by ex vivo IFN-gamma ELISPOT assay. The T-cell population could be further characterized by 4-color flow cytometry in 1 patient, showing that the majority of the peptide-specific CD3(+)CD8(+)IFN-gamma(+) T cells were granzyme B-positive and CCR-7-negative, characterizing them as effector T cells with the ability to mediate cytotoxicity and migrate to inflamed tissues. In this patient also, augmentation of the T-cell response to autologous tumor cells by vaccination could be detected. A single-site postvaccination relapse occurred in both patients, showing downregulation of tyrosinase expression in 1 patient, while normal expression levels for tyrosinase, MHC class I antigens and components of the antigen-processing machinery were found in the other patient. These results suggest that peptide vaccination resulted in a prolonged relapse-free interval in these high-risk patients.
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PMID:Long-term freedom from recurrence in 2 stage IV melanoma patients following vaccination with tyrosinase peptides. 1199 9

Primary bony lymphomas are rare, and nearly all are high-grade B-cell lymphomas. Natural killer (NK)/T-cell lymphomas are highly aggressive lymphomas of NK- or T-cell lineage with predominant extranodal presentation and are divided into nasal and nasal-type (extra-nasal). We report a primary bony peripheral T-cell lymphoma mimicking NK/T-cell lymphoma, nasal type. A 22-year-old Taiwanese male presented with a frontal skull bone mass noted for 3 weeks, and received craniectomy with tumor removal. His tumor showed extensive coagulative necrosis with angioinvasion by large lymphoma cells expressing CD2, CD8, CD16, CD43, CD45, CD45RO, CD56, T-cell intracellular antigen-1, and granzyme B, but not CD3, CD4, CD20, CD57, CD68, and betaF1. In situ hybridization for Epstein-Barr virus-encoded mRNA was negative. Polymerase chain reaction study of formalin-fixed tissue showed clonal rearrangement of the T-cell receptor-gamma chain gene. The diagnosis was peripheral T-cell lymphoma, unspecified subtype. The initial stage was I(EA). His lymphoma was refractory to chemotherapy, and bony metastases developed in the right iliac bone 2 months later. He died of disease after 6 months without autopsy. We emphasize the importance of detailed immunohistochemical and gene rearrangement studies for the classification of malignant lymphomas via a very rare primary bony lymphoma of peripheral T-cell subtype.
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PMID:Primary bony peripheral T-cell lymphoma mimicking nasal type NK/T-cell lymphoma: a case report. 1209 74

A case of a nasal-type NK/T cell lymphoma of the orbit with distant metastases is reported. The orbital lymphoma was angiodestructive with prominent necrosis and frequent apoptosis. Lymphoma cells were positive for CD56, cytotoxic molecules (granzyme B and TIA-1), and EBV. Despite local radiotherapy, the patient had a highly aggressive clinical course. A postmortem examination revealed distant metastases to the heart and lungs exhibiting angiocentric growth. TCR and Ig genes of a cardiac lesion were in germ line configuration. This case demonstrated that nasal-type NK/T cell lymphomas with a poor prognosis can occur in the orbit.
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PMID:Nasal-type NK/T cell lymphoma of the orbit with distant metastases. 1267 66

Activation of CTL-mediated antitumor immunity to self-epitopes expressed by neoplastic cells is thought to be prevented, at any stage of tumor progression, by tolerance mechanisms. In contrast, in 74 American Joint Committee on Cancer stages I-IV melanoma patients, we found that development of lymph node metastases is a key event triggering CD8(+) T-cell-mediated immunity to self-epitopes encoded by melanocyte differentiation antigens. This was shown by the increased peripheral precursor frequency to Melan-A/Mart-1, gp100, and tyrosinase epitopes in stage III and IV compared with stage I and II patients, and by accumulation of functional memory T cells directed to Melan-A/Mart-1(26-35) in tumor-invaded lymph nodes. However, in tumor-invaded lymph nodes of most patients, CD8(+) T cells directed to melanocyte differentiation antigens or to tumor-restricted antigens (MAGE-3 and NY-ESO-1 epitopes), showed a CCR7(+) CD45RA(+) CD27(+) CD28(+) perforin(-) "precursor" phenotype. Only in 7 of 23 cases antigen-specific CD8(+) T cells in invaded lymph nodes showed a predominant CCR7(-) CD45RA(-) CD27(+) CD28(-) perforin(+) "preterminally differentiated" phenotype. In the latter subset of patients, by immunohistochemistry in lymph node lesions, we found that CD8(+) T lymphocytes intermingling with the neoplastic tissue expressed a CCR7(-) CD45RO(+)/RA(-) phenotype, whereas CD4(+) lymphocytes did not infiltrate the tumor. Furthermore, perforin and granzyme B were expressed on a higher fraction of the CD8(+) cells surrounding the invading tumor compared with the lymphocytes infiltrating the neoplastic tissue. In addition, no evidence for tumor regression was found in such metastatic lesions, as documented by absence of neoplastic cell necrosis or apoptosis. These data indicate that neoplastic cells in the lymph nodes and/or increased tumor burden in metastatic disease activate CD8(+) T-cell-mediated antitumor immunity to self-epitopes. However, the paucity of terminally differentiated CD8(+) T cells at tumor site suggests that immunotherapy strategies may require not only the boosting of tumor immunity, but also effective means to promote CD8(+) T-cell differentiation in the neoplastic tissue.
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PMID:Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. 1275 Feb 77

In order to form distant metastases, cells from the primary tumor have to detach, enter the blood- or lymph-compartment and escape immune surveillance. Here, we describe the selection of rat colon carcinoma cell lines (CC531s-m1 and CC531s-m2) that escaped from systemic immune surveillance; CC531s cells were injected into the v. jugularis of Wag/Rij rats, after three weeks the lung tumors were isolated, the tumor cells were cultured, characterized and injected again. The m1- and m2-cell lines were less susceptible for killing by syngeneic NK cells. Further characterization of this cell line showed a decreased sensitivity towards TRAIL- and CD95L-, but not to granzyme B-mediated apoptosis. In the m1- and m2-cells log-phase growth started earlier as compared to the parental cell line, whereas no changes were found in anchorage-dependent or anchorage-independent growth. After subcapsular injection of the m2-cell line into the liver of rats much more lung metastases were formed in comparison to injection of the parental cell line. In conclusion, the results suggest that the resistance of the m1- and m2-cells to NK cell-mediated apoptosis was associated with their capability to survive systemic immune surveillance and form metastases in vivo.
Clin Exp Metastasis 2003
PMID:Rat colon carcinoma cells that survived systemic immune surveillance are less sensitive to NK-cell mediated apoptosis. 1471 5

Recently, we showed that Epstein-Barr virus (EBV)-positive gastric carcinoma (GC) forms a distinct clinicopathologic entity with a better prognosis due to lower incidence of lymph node metastases (LN+). Here we investigated whether in EBV-positive GC more pronounced activation of cellular immune responses is associated with absence of (micro)metastases. Twenty EBV-positive primary tumors (PT) (9 LN+) were matched with 28 EBV-negative GC (11 LN+) for T- and N-stage, gender, and age. The PT (n = 28) and its LNs were analyzed by EBER RNA in situ hybridization and by immunohistochemistry for MHC class I and II expression, for CD3, CD8, CD4, CD20, CD56, CD83, and Granzyme B (GzB) expression. In LN metastases of EBV-positive GC, the EBV genome is maintained, excluding tumor escape by virus deletion. All GC express MHC class I independently of EBV status. In comparison with EBV-negative GC, EBV-positive GC have higher expression of MHC class II on the tumor cells (P = 0.029) and a more extensive infiltrate (P < 0.0001) of activated GzB+ CD8+ T cells (P = 0.028), which is most abundant in those EBV-positive tumors that do not metastasize (P < 0.0001). In addition, in EBV-positive GC without metastases, the infiltrate contains higher numbers of mature dendritic cells (DC) (P = 0.018). At present, the antigenic target has to be determined. These data support the notion that local triggering of cellular immune responses in EBV-positive GC prevents lymph node metastasis formation.
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PMID:Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases. 1633 Sep 43

It is still controversial whether keratoacanthoma is to be considered as a well differentiated variant of squamous cell-carcinoma or a separate entity. As opposed to malignant potential of squamous cell-carcinoma, keratoacanthoma is characterized by a spontaneous regression. However, in some cases, otherwise typical keratoacanthoma can behave aggressively showing the signs of perineural and perivascular invasion and metastases in regional lymph nodes. The most important feature that separates these two closely related entities is a tendency of keratoacanthoma to regress. Causes and detailed mechanism of this regression are still not completely elucidated. Within the past few years, it has become evident that the molecular events regulating cell survival and apoptosis are important contributors to the overall kinetics of benign and malignant cell growth. Immunological mechanisms have been implicated in a phenomenon of spontaneous tumor regression. Recent studies suggested that the tumor regression is dependent mainly on the immune response mediated by cytotoxic T lymphocytes (CD8+), together with helper T cells (CD4+). Cytotoxic T lymphocytes can kill tumor cells and mediate tumor regression in vivo through two distinct molecular mechanisms: Fas/Fas ligand and granzyme B/perforin mediated pathways. Tumor cells are capable of developing different escape mechanisms in order to overcome their sensitivity to apoptotic signals. However, granzyme B, contained in cytolytic granules released upon target cell recognition, can also cause tumor cell death and consequently tumor regression by direct damage to non-nuclear structures through a caspase-independent pathway. Therefore, we propose a key role of plasticity in the granzyme B mediated cell death pathway in the killing of changed tumor cells, resulting in keratoacanthoma regression through apoptosis or direct damage of tumor cells. On the other hand, insufficient activation of cytotoxic T lymphocytes and decreased release or activity of granzyme B could be responsible for squamous cell-carcinoma progression and occasional aggressive behavior in keratoacanthomas. As a first step in confirming or refuting our hypothesis, we suggest a thorough immunohistochemical study of the presence of granzyme B and its activity in keratoacanthoma and squamous cell-carcinoma samples. To our knowledge, no such study has been performed so far.
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PMID:Possible key role of granzyme B in keratoacanthoma regression. 1649 44


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