PubMed · 14132815
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J SWIERENGA. 1964-03-28. [PLEURAL EXUDATES].. https://pubmed.ncbi.nlm.nih.gov/14132815/
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The nuclear pore complex protein Nup88 is overexpressed in tumor cells. Immunohistochemical studies have shown that this overexpression is linked to higher aggressiveness of colorectal carcinoma and to enhanced metastatic potential of melanoma cells. However, the antibodies so far developed against Nup88 have the drawback of recognizing a number of other, up to now unspecified antigens besides Nup88. For this reason, we devised the present study on Nup88 expression at the mRNA level. RNA was extracted from fresh tumor tissue corresponding to 122 breast cancer patients. Nup88 mRNA expression was measured by means of differential RT-PCR, standardizing against a constitutive internal control gene (beta-actin). The results were dichotomized into "high" and "low" expression levels, using the median value as cut-off. High Nup88 mRNA expression levels correlated significantly with ductal and tubular histology (p = 0.012), histologic and nuclear grade 3 of tumors (p < 0.001), absence of hormone receptor expression (p < 0.001), expression of the c-erb-B2 oncogene (p < 0.001), expression of mutant p53 protein (p < 0.001), high proliferation (defined by Ki67 labeling index >20%, p < 0.001), DNA aneuploidy (p < 0.001) as well as the most important ominous clinical prognostic factor, axillary node invasion (p < 0.001). We also found an inverse correlation (p < 0.001) with expression of the H-MAM (mammaglobin) gene, a marker of low biologic and clinical aggressiveness of breast cancer. All of these factors, without exception, define a highly aggressive tumor phenotype. These findings appear to be specific to Nup88 and not to nuclear pore proteins in general. Indeed, analysis of Nup107 (which is a limiting component of the nuclear pore complex) under the same conditions in the same tumors did not yield comparable results.
Although there are several ways to load tumor antigens to DCs, in vitro preparation of tumor antigens and manipulation of DCs are usually required. Therefore, to develop a simple antitumor immunization method, we examined if direct injection of DCs into tumor apoptosed by ionizing IR could induce efficient antitumor immunity. Ionizing IR with 15 Gy induced apoptosis in tumor maximally after 6 hr. Injection of DCs i.t. into IR tumor induced strong cytotoxicity of splenocytes against tumor cells compared to i.t. injection of DCs or ionizing IR of tumor, both of which induced weak cytotoxicity. In an animal study, i.t. injection of DCs into IR tumor induced therapeutic antitumor immunity against a tumor established at a distant site. Moreover, when TNF-alpha or LPS was added as a danger/maturation signal to DC suspension before i.t. injection, antitumor immunity was significantly potentiated compared to a group treated with i.t. injection of DCs into IR tumor. Our results suggest that injection of DCs into tumor apoptosed by ionizing IR might be a simple and efficient method of immunization against tumor.
BACKGROUND: There is increasing evidence to suggest that dendritic cells (DC) are functionally impaired in tumor bearing hosts. However there is little or no data on the effects of murine prostate cancer (CaP) on DC generation from bone marrow precursors. METHODS: Flow cytometry, mixed leukocyte reactions (MLR), and immunohistochemical analyses were used to characterize DC in CaP. RESULTS: DC generated in the presence of CaP cell lines RM1 and the cell line C2 from the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse in a Transwell system expressed significantly lower levels of DC differentiation markers. This effect was confirmed when TK-neo-transfected RM1 cells were directly added to DC cultures and eliminated 5 days later using gancyclovir (GCV). Furthermore, co-incubation of DC with CaP cells resulted in a decrease in the stimulatory capacity of DC to induce T cell proliferation in the MLR assay. These results were further confirmed in vivo in two different murine models of CaP: i) DC generated from mice intrafemorally injected with TK-neo-transfected RM1 cells; and ii) in DC generated from TRAMP mice. CONCLUSIONS: The generation and function of DC are significantly suppressed in the CaP microenvironment in both in vivo and in vitro murine models.