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

Murine liver contains alpha beta T cells with intermediate TCR (TCRint) as well as alpha beta T cells with bright TCR. Liver TCRint cells express NK1.1 Ag (NK1+ TCRint) and IL-2 receptor beta chain, both of which are NK cell markers and are not expressed on conventional T cells. Liver NK1+ TCRint cells consist of CD4-8- double negative T cells and CD4+ T cells and have V beta 8+ T cell preponderance. They are dependent on class Ib or CD1 molecules of APC for their development. They can also develop thymus independent manner, because athymic nude mice have this population. These NK1+ TCRint cells in the livers of both euthymic and athymic mice were found to be activated by systemic administration of IL-12 and increased NK1 expression (NK1high TCRint) and cytotoxicity against various NK-sensitive and resistant tumors. Cytotoxicity assays after treatment of IL-12 stimulated hepatic MNC with respective Abs and C revealed that CD4+ NK1high TCRint cells are responsible for IL-12 induced cytotoxicity. Although NK1+ TCRint cells were normally few in the lungs, a significant proportion of NK1high TCRint cells with strong cytotoxicity was also induced in the lung by IL-12. Interestingly, adoptive transfer of IL-12 stimulated hepatic MNC into other mice, which were pre-injected with tumors, inhibits hepatic metastases of EL4 cells and pulmonary metastases of 3LL cells as similarly as IL-12 administration. Transfer experiments after treatment of IL-12 stimulated hepatic MNC with respective Ab and C revealed that depletion of either NK1+ cells, CD3+ cells or CD4+ cells but not CD8+ cells greatly impaired antimetastatic effect in both organs. Thus, CD4+ NK1high TCRint cells are a major antimetastatic population, especially, against hematogenous metastases.
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PMID:[The function and role of extrathymic T cells]. 853 54

The purpose of this study was to investigate the relationship between changes in density and distribution of dendritic cells, both in epidermis and in peritumoral infiltrate, and lymphocyte subset variations in malignant melanomas (MM) of patients belonging to different risk groups. The collective immunoreactive expression of six markers (S100 protein, CD1-a, HLA-DR, CD4, CD8 and CD25) was analyzed in 13 cutaneous malignant melanomas. Changes were observed in density and distribution of Langerhans cells (LC) (S100+, CD1-a+) in the epidermis overlying the tumor, as well as in peritumoral and intratumoral locations, independently of the tumor-invasion level. A decrease was recorded in LC (S100+, CD1-a+) in the epidermis overlying six tumors, whereas most of the MM studied showed an increase of LC (S100+, CD1-a+) in peritumoral infiltrate. The expression of HLA-DR in tumor cells was controversial; it was observed in three moderate-risk MM, but it was negative in high-risk tumors. The percentage of CD4+ cells was in most cases greater than that of CD8+ in the peritumoral infiltrate, irrespective of the degree of histopathological malignancy. The concomitant expression of the lymphocytic activation marker CD25 (receptor for interleukin 2) in lymphocytic infiltrate was variable. Peritumoral infiltrate in three high risk MM contained few CD25+ cells, and a concomitant decrease was recorded in LC. This preliminary report shows that alterations in the density and distribution of LC may be responsible for determining the degree or T lymphocyte activation, and this may be critical for the development of effective tumor-directed immunity. Further studies are required to demonstrate these hypothetical interrelations.
Invasion Metastasis 1995
PMID:Immunophenotype analysis of dendritic cells and lymphocytes associated with cutaneous malignant melanomas. 862 Dec 68

Ewing's sarcoma shows a strong tendency to metastasize to the lungs or the skeleton, or both. A peculiar feature of the secondary involvement of bone with this tumor is that it may also appear in the absence of clinically evident lung metastases, both at clinical presentation and during the course of the disease. Although osseous metastases are critically relevant for prognosis, the pathogenesis of this peculiar feature of Ewing's sarcoma is poorly understood, partly due to the lack of appropriate experimental in vivo models. We show that the intravenous injection of TC-71 Ewing's sarcoma cells into athymic 4-5-week-old Crl/nu/nu (CD1) BR mice reproducibly colonizes specific sites of the skeleton in addition to the lungs and lymph nodes. The distribution and the morphologic appearance of these experimental bone metastases mimic the pattern of skeletal involvement observed in humans. This experimental model of bone metastasis of Ewing's sarcoma may be the basis for future studies aimed at understanding the pathophysiology and treatment of Ewing's sarcoma.
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PMID:Murine model for skeletal metastases of Ewing's sarcoma. 1119 57

The role of Langerhans cells as antigen-presenting cells was examined in cervical carcinomas. Frozen samples were obtained from 34 women with stage Ib and II cervical carcinomas. Langerhans cells (CD1), T lymphocytes (CD4 and CD8), B lymphocytes (CD22), and natural killer (CD57, NK) cells were all quantitatively assessed in cervical carcinomas using immunohistochemical methods. These results were related to the MHC class I and II expression on the tumor cells. The majority of Langerhans cells were distributed among cancer cells and they were positively correlated with CD4+, NK and B cells in cervical carcinomas. This is suggestive of the presence of local immune response. The numbers of Langerhans, CD4+, CD8+ and NK cells did not significantly correlate with age at operation, lymph node metastases or depth of cervical wall invasion. The downregulation of MHC class I expression found in 8 (24%) carcinomas was not associated with the decrease in the number of immunologic cells. The upregulation of MHC class II expression found in 26 (76%) carcinomas was significantly associated with the increase in the number of Langerhans cells (p < 0.007). However, the association between the upregulation of MHC-II expression and CD4+ cells did not reach statistical significance (p < 0.07). This is probably due to a small case in this study. MHC-II-restricted immunity may partly contribute to the local immune response in stages Ib and II squamous cell carcinoma of the uterine cervix.
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PMID:Local immune response in squamous cell carcinoma of the uterine cervix. 1154 55

Photodynamic therapy (PDT), locally applied to solid C6 rat glioma tumors in the foot of CD1 nude mice, eradicated the primary tumor and also decreased the rate of groin and lung metastases. Pd-Bacteriopheophorbide (Pd-Bpheid), a novel photosensitizer synthesized in our laboratory, was used in our study. The primary lesion in the hind leg was treated by an i.v. injection of 5 mg/kg of Pd-Bpheid and immediate illumination (650-800 nm, 360 J/cm(2)). This protocol and the surgical amputation of the leg were compared for local and metastasis responses. Following PDT, hemorrhage, inflammation with tumor necrosis and flattening were observed and histologically verified in the photodynamically treated tumor. Whereas local tumor control rates were up to 64% following PDT, in surgically treated animals, local tumor control was absolute. The rates of metastases in the groin and the lungs were at least 12-fold lower in the photodynamically treated animals compared with untreated or surgery-treated groups. The overall cure rates after PDT or surgery were 36% and 6%, respectively, at 8 weeks. These findings suggest that local PDT with Pd-Bpheid, which acts primarily on the tumor vasculature, efficiently eradicates the solid C6 tumors. In addition, the local PDT of the primary lesion has beneficial therapeutic effects on remote C6 metastasis, which is not obtained with surgery. It is therefore suggested, that although surgery is highly efficient for the immediate removal of the primary tumor, it lacks such systemic, therapeutic effects on distant metastases. Pd-Bpheid-PDT may thus offer a potentially superior curative therapy for C6 glioma tumors in the limb by eradicating the target tumor and by reducing the rate of metastasis in the groin and lung, possibly due to innate immunity.
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PMID:Local photodynamic therapy (PDT) of rat C6 glioma xenografts with Pd-bacteriopheophorbide leads to decreased metastases and increase of animal cure compared with surgery. 1197 45

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

Small cell carcinoma of the prostate (SCCP), although relatively rare, is the most aggressive variant of prostate cancer, currently with no successful treatment. It was therefore tempting to evaluate the response of this violent malignancy and its bone lesions to Pd-Bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT), already proven by us to efficiently eradicate other aggressive non-epithelial solid tumors. TOOKAD is a novel bacteriochlorophyll-derived, second-generation photosensitizer recently, developed by us for the treatment of bulky tumors. This photosensitizer is endowed with strong light absorbance (epsilon(0) approximately 10(5) mol(-1) cm(-1)) in the near infrared region (lambda=763nm), allowing deep tissue penetration. The TOOKAD-PDT protocol targets the tumor vasculature leading to inflammation, hypoxia, necrosis and tumor eradication. The sensitizer clears rapidly from the circulation within a few hours and does not accumulate in tissues, which is compatible with the treatment of localized tumor and isolated metastases. Briefly, male CD1-nude mice were grafted with the human SCCP (WISH-PC2) in 3 relevant anatomic locations: subcutaneous (representing tumor mass), intraosseous (representing bone metastases) and orthotopically within the murine prostate microenvironment. The PDT protocol consisted of i.v. administration of TOOKAD (4 mg/kg), followed by immediate illumination (650-800 nm) from a xenon light source or a diode laser emitting at 770 nm. Controls included untreated animals or animals treated with light or TOOKAD alone. Tumor volume, human plasma chromogranin A levels, animal well being and survival were used as end points. In addition, histopathology and immunohistochemistry were used to define the tumor response. Subcutaneous tumors exhibited complete healing within 28-40 days, reaching an overall long-term cure rate of 69%, followed for 90 days after PDT. Intratibial WISH-PC2 lesions responded with complete tumor elimination in 50% of the treated mice at 70-90 days after PDT as documented histologically. The response of the orthotopic model was also analyzed histologically with similar results. The study with this model suggests that TOOKAD-based PDT can reach large tumors and is a feasible, efficient and well-tolerated approach for minimally invasive treatment of local and disseminated SCCP.
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PMID:Photodynamic therapy with Pd-Bacteriopheophorbide (TOOKAD): successful in vivo treatment of human prostatic small cell carcinoma xenografts. 1264 Jun 88

Many tumor immunologists favor the hypothesis that optimal anti-tumor activity is mediated by type 1 CD4(+) and CD8(+) T cells, and that the production of type 2 CD4(+) T cells may be counterproductive for effective anti-tumor immunity. Since Stat6-deficient or "knockout" mice lack the signal transducer and activator of transcription-6 protein and are unable to transmit signals initiated by the type 2 cytokines, IL-4 and IL-13, they have been studied to confirm the T(h)1 vs T(h)2 paradigm. Using transplantable tumor cells that cause primary solid tumors and metastatic disease, as well as a spontaneous transgenic tumor model, multiple studies have demonstrated that Stat6(-/-) mice are able to reject or delay primary tumor growth, prevent recurrence of primary tumors, and/or reject established, spontaneous metastatic disease. Deletion of the Stat6 gene, therefore, provides significantly enhanced immunosurveillance. Comparable experiments with CD1-deficient mice, which lack NKT cells and hence are deficient for IL-13, give similar results and suggest that removal of NKT cells also enhances immunosurveillance. Because immunity is enhanced in the absence of Stat6 or CD1, it has been hypothesized that these deletions result in the removal of an inhibitor that blocks constitutive immunosurveillance. Several mechanisms have been tested as potential inhibitors, including CD4(+)CD25(+) T regulatory cells, IL-13, a T(h)2 shift, and myeloid suppressor cells. Although the first three mechanisms do not appear to be relevant, regression of myeloid suppressor cells in Stat6-deficient and CD1-deficient mice may be responsible for enhanced immunosurveillance. Although additional studies are clearly needed to clarify the mechanism(s) underlying improved anti-tumor immunity in Stat6(-/-) and CD1(-/-) mice, deletion of these genes results in a potent anti-tumor immunity and may be a basis for an immunotherapy strategy.
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PMID:Signal transducer and activator of transcription 6 (Stat6) and CD1: inhibitors of immunosurveillance against primary tumors and metastatic disease. 1459 99

While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1(-/-) DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8(+) cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4(+) not CD8(+) T cells were required for induction of the NK antitumor response. The role of DCs and CD4(+) T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.
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PMID:Dendritic cell-induced activation of adaptive and innate antitumor immunity. 1463 94

We have previously observed a novel role of natural killer T (NKT) cells in negative regulation of antitumor immune responses against an immunogenic regressor tumor expressing a transfected viral antigen. Here, we investigated whether hidden spontaneous antitumor immunosurveillance, in the absence of a vaccine, could be revealed by disruption of this negative regulatory pathway involving CD4+ NKT cells and interleukin-13 (IL-13), in a murine pulmonary metastasis model of a nontransfected, nonregressor, syngeneic tumor, the CT26 colon carcinoma. Lung metastases of CT26 were decreased in CD4+ T cell-depleted BALB/c mice, suggesting that CD4+ T cells were involved in negative regulation of antitumor responses. CD1-knock out (CD1-KO) mice, which have conventional CD4+ T cells and CD4+CD25+ regulatory T cells but lack CD1-restricted CD4+ NKT cells, were significantly resistant to lung metastasis of CT26. The metastases were not further decreased in CD4+ T cell-depleted CD1-KO mice, implying that CD4+ NKT cells might be the primary negative regulator of antitumor immune responses in BALB/c mice. CD8+ T cells were found to act as effectors in antitumor immune responses, since the inhibition of lung metastases observed in naive CD1-KO or CD4+ T cell-depleted mice was abrogated by depletion of CD8+ T cells. Lung metastases were significantly decreased by treatment of mice with an IL-13 inhibitor, but not by deficiency or inhibition of IL-4. Thus, even for a nonregressor tumor, immunosurveillance exists but is negatively regulated via CD4+ NKT cells possibly mediated by IL-13, and can be unmasked by removal of these negative regulatory components.
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PMID:Unmasking immunosurveillance against a syngeneic colon cancer by elimination of CD4+ NKT regulatory cells and IL-13. 1552 92


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