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Simple Summary: The evidence reviewed here indicates that MUC1-C evolved in mammals to promote inflammatory adaptation in barrier tissues that extends to resident stem cells and immune cells. Inflammatory memory is an essential process that protects barrier niches against future insults. Evolutionary adaptations arising from natural selection, as for example the MUC1 gene, can be beneficial for survival. However, prolonged activation of MUC1-C in settings of chronic inflammation represents an adverse adaptation that promotes cancer. The mucin 1 (MUC1) gene was discovered based on its overexpression in human breast cancers. Subsequent work demonstrated that MUC1 is aberrantly expressed in cancers originating from other diverse organs, including skin and immune cells. These findings supported a role for MUC1 in the adaptation of barrier tissues to infection and environmental stress. Of fundamental importance for this evolutionary adaptation was inclusion of a SEA domain, which catalyzes autoproteolysis of the MUC1 protein and formation of a non-covalent heterodimeric complex. The resulting MUC1 heterodimer is poised at the apical cell membrane to respond to loss of homeostasis. Disruption of the complex releases the MUC1 N-terminal (MUC1-N) subunit into a protective mucous gel. Conversely, the transmembrane C-terminal (MUC1-C) subunit activates a program of lineage plasticity, epigenetic reprogramming and repair. This MUC1-C-activated program apparently evolved for barrier tissues to mount self-regulating proliferative, inflammatory and remodeling responses associated with wound healing. Emerging evidence indicates that MUC1-C underpins inflammatory adaptation of tissue stem cells and immune cells in the barrier niche. This review focuses on how prolonged activation of MUC1-C by chronic inflammation in these niches promotes the cancer stem cell (CSC) state by establishing auto-inductive nodes that drive self-renewal and tumorigenicity. [ABSTRACT FROM AUTHOR]

The effects of human angiostatin on primary tumour growth were assessed by treating mice with murine Lewis lung carcinoma (LLC) tumours with angiostatin. The interaction of the antitumour effects of angiostatin and ionizing radiation was seen at concentrations of angiostatin which had small effects on primary tumour growth. This may be due to the large tumour volumes used in the experiment compared to other studies.

The involvement of the c-abl gene in cells' stress response to DNA-damaging agents is demonstrated by its kinase activation when exposed to ionizing radiation. The failure of the c-Abl tyrosine kinase deficient cells to activate the Jun kinase also indicates c-Abl's importance in the stress response. However, c-Abl does not appear to be involved in the response to tumor-necrosis factor because it is not stimulated.

A signal transduction pathway catalyzes protein kinase C activation, radiation-mediated production of arachidonic acid and tumor neurosis factor alpha gene induction by x-rays. Phospholipase A2 inhibition reduces arachidonic acid level, indicating the regulation of the radiation-mediated gene expression by the signal transduction pathway in human cells. Phospholipase A2 inhibitors reduce the negative effects of radiotherapy during necrosis factor production.

Ionizing radiation can increase the expression of the early growth response 1 gene (EGR1). The signaling events mediating the induction of EGR1 by ionizing radiation were elucidated. The results showed that the increased expression of EGR1 is associated with the formation of reactive oxygen intermediates (ROIs). Similar intermediates were formed in response to exposure of cells to hydrogen peroxide. The ROIs increase the expression of EGR1 by activating serum response elements, which in turn induce EGR1 transcription.

Ionizing radiation-induced transcription of the c-jun gene is partly mediated by reactive oxygen intermediates (ROIs) in HL-525 cells which are HL-60 cell variants deficient in the alpha and beta isoforms of protein kinase C. The induction of gene transcription was shown to be inhibited by a non-specific inhibitor of protein kinase C, H7, and not by one that is specific for cyclic nucleotide-dependent kinase, HA1004. This indicate that in addition to ROIs, another isoform of protein kinase C distinct from the alpha and beta forms may mediate the induction of c-jun transcription.

Abstract Background MUC1 protein is highly expressed in lung cancer. The cytoplasmic domain of MUC1 (MUC1-CD) induces tumorigenesis and resistance to DNA-damaging agents. We characterized MUC1-CD-induced transcriptional changes and examined their significance in lung cancer patients. Methods Using DNA microarrays, we identified 254 genes that were differentially expressed in cell lines transformed by MUC1-CD compared to control cell lines. We then examined expression of these genes in 441 lung adenocarcinomas from a publicly available database. We employed statistical analyses independent of clinical outcomes, including hierarchical clustering, Student's t-tests and receiver operating characteristic (ROC) analysis, to select a seven-gene MUC1-associated proliferation signature (MAPS). We demonstrated the prognostic value of MAPS in this database using Kaplan-Meier survival analysis, log-rank tests and Cox models. The MAPS was further validated for prognostic significance in 84 lung adenocarcinoma patients from an independent database. Results MAPS genes were found to be associated with proliferation and cell cycle regulation and included CCNB1, CDC2, CDC20, CDKN3, MAD2L1, PRC1 and RRM2. MAPS expressors (MAPS+) had inferior survival compared to non-expressors (MAPS-). In the initial data set, 5-year survival was 65% (MAPS-) vs. 45% (MAPS+, p < 0.0001). Similarly, in the validation data set, 5-year survival was 57% (MAPS-) vs. 28% (MAPS+, p = 0.005). Conclusions The MAPS signature, comprised of MUC1-CD-dependent genes involved in the control of cell cycle and proliferation, is associated with poor outcomes in patients with adenocarcinoma of the lung. These data provide potential new prognostic biomarkers and treatment targets for lung adenocarcinoma.

Chronic inflammation is a highly prevalent consequence of changes in environmental and lifestyle factors that contribute to the development of cancer. The basis for this critical association has largely remained unclear. The MUC1 gene evolved in mammals to protect epithelia from the external environment. The MUC1-C subunit promotes responses found in wound healing and cancer. MUC1-C induces EMT, epigenetic reprogramming, dedifferentiation and pluripotency factor expression, which when prolonged in chronic inflammation promote cancer progression. As discussed in this review, MUC1-C also drives drug resistance and immune evasion, and is an important target for cancer therapeutics now under development. [ABSTRACT FROM AUTHOR]

Author(s): Donald W. Kufe [1] Despite progress in the treatment of cancer with surgery, radiotherapy and chemotherapy, only incremental advances have been made in improving survival rates, particularly in patients [...]

CBP501 is an anti-cancer drug candidate which has been shown to increase cis-diamminedichloro-platinum (II) (CDDP) uptake into cancer cell through calmodulin (CaM) inhibition. However, the effects of CBP501 on the cells in the tumor microenvironment have not been addressed. Here, we investigated new aspects of the potential anti-tumor mechanism of action of CBP501 by examining its effects on the macrophages. Macrophages contribute to cancer-related inflammation and sequential production of cytokines such as IL-6 and TNF-α which cause various biological processes that promote tumor initiation, growth and metastasis (1). These processes include the epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) formation, which are well-known, key events for metastasis. The present work demonstrates that CBP501 suppresses lipopolysaccharide (LPS)-induced production of IL-6, IL-10 and TNF-α by macrophages. CBP501 also suppressed formation of the tumor spheroids by culturing with conditioned medium from the LPS-stimulated macrophage cell line RAW264.7. Moreover, CBP501 suppressed expression of ABCG2, a marker for CSCs, by inhibiting the interaction between cancer cells expressing VCAM-1 and macrophages expressing VLA-4. Consistently with these results, CBP501 in vivo suppressed metastases of a tumor cell line, 4T1, one which is insensitive to combination treatment of CBP501 and CDDP in vitro. Taken together, these results offer potential new, unanticipated advantages of CBP501 treatment in anti-tumor therapy through a mechanism that entails the suppression of interactions between macrophages and cancer cells with suppression of sequential CSC-like cell formation in the tumor microenvironment.

Background: MUC1 protein is highly expressed in lung cancer. The cytoplasmic domain of MUC1 (MUC1-CD) induces tumorigenesis and resistance to DNA-damaging agents. We characterized MUC1-CD-induced transcriptional changes and examined their significance in lung cancer patients. Methods: Using DNA microarrays, we identified 254 genes that were differentially expressed in cell lines transformed by MUC1-CD compared to control cell lines. We then examined expression of these genes in 441 lung adenocarcinomas from a publicly available database. We employed statistical analyses independent of clinical outcomes, including hierarchical clustering, Student's t-tests and receiver operating characteristic (ROC) analysis, to select a seven-gene MUC1-associated proliferation signature (MAPS). We demonstrated the prognostic value of MAPS in this database using Kaplan-Meier survival analysis, log-rank tests and Cox models. The MAPS was further validated for prognostic significance in 84 lung adenocarcinoma patients from an independent database. Results: MAPS genes were found to be associated with proliferation and cell cycle regulation and included CCNB1, CDC2, CDC20, CDKN3, MAD2L1, PRC1 and RRM2. MAPS expressors (MAPS+) had inferior survival compared to nonexpressors (MAPS-). In the initial data set, 5-year survival was 65% (MAPS-) vs. 45% (MAPS+, p < 0.0001). Similarly, in the validation data set, 5-year survival was 57% (MAPS-) vs. 28% (MAPS+, p = 0.005). Conclusions: The MAPS signature, comprised of MUC1-CD-dependent genes involved in the control of cell cycle and proliferation, is associated with poor outcomes in patients with adenocarcinoma of the lung. These data provide potential new prognostic biomarkers and treatment targets for lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Epithelia are protected from adverse conditions by a mucous barrier. The secreted and transmembrane mucins that constitute the mucous barrier are largely unrecognized as effectors of carcinogenesis. However, both types of mucins are intimately involved in inflammation and cancer. Moreover, diverse human malignancies overexpress transmembrane mucins to exploit their role in signalling cell growth and survival. Mucins have thus been identified as markers of adverse prognosis and as attractive therapeutic targets. Notably, the findings that certain transmembrane mucins induce transformation and promote tumour progression have provided the experimental basis for demonstrating that inhibitors of their function are effective as anti-tumour agents in preclinical models. [ABSTRACT FROM AUTHOR]

The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in human breast cancers. Although MUC1 modulates the activity of estrogen receptor α (ER), there is no information regarding the effects of MUC1 on global gene expression patterns and the potential role of MUC1-induced genes in predicting outcome for breast cancer patients. We have developed an experimental model of MUC1-induced transformation that has identified the activation of genes involved in cholesterol and fatty acid metabolism. A 38-gene set of experimentally derived MUC1-induced genes associated with lipid metabolism was applied to the analysis of ER+ breast cancer patients treated with tamoxifen. The results obtained from 2 independent databases demonstrate that patients overexpressing MUC1 and the lipid metabolic pathways are at significantly higher risk for death and recurrence/distant metastasis. By contrast, these genes were not predictive in untreated patients. Furthermore, a positive correlation was found between expression of the 38-gene set and the ER signaling pathway. These findings indicate that (i) MUC1 regulates cholesterol and fatty acid metabolism, and (ii) activation of these pathways in ER+ breast cancers predicts failure to tamoxifen treatment. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) cells express certain tumour-associated antigens (TAAs) that could serve as targets for active-specific immunotherapy. The aim of the present study was to test the MM/dendritic cell (DC) fusion as a vaccination strategy. We fused MM cells with DC to generate fusion cells (FCs) and tested their antigen presenting cell (APC) function in mixed lymphocyte reactions and cytotoxicity assays. First, the HS Sultan and SK0-007 HAT sensitive human MM cell lines and DCs generated from peripheral blood of normal donors were fused in the presence of 50% polyethylene glycol to form FCs. Next, tumour cells freshly isolated from patients were similarly fused with autologous DCs to generate FCs. The FCs demonstrated a biphenotypic profile, confirmed both by flow-cytometry and dual immunofluorescence microscopy. These FCs induced MM-specific cytotoxicity. FCs, but not MM cells or DCs alone, were potent stimulators of autologous patient T cells. More importantly, FC-primed autologous peripheral blood mononuclear cells demonstrated major histocompatibility complex-restricted MM-specific cytolysis. These studies therefore demonstrated that MM/DC FC can trigger an autologous immune response to MM cells and formed the framework for a clinical trial currently underway. [ABSTRACT FROM AUTHOR]

Investigates the role of vascular endothelial growth factor in tumor response to ionizing radiation. Use of mean fractional tumor volume to evaluate treatment efficacy; Enhancement of the surviving fraction of endothelial cells; Demonstration on the importance of genetics as determinants of radiocurability.

The full promise of gene therapy has been limited by the lack of specificity of vectors for tumor tissue as well as the lack of antitumor efficacy of transgenes encoded by gene delivery systems. In this paper we review our studies investigating two modifications of gene therapy combined with radiotherapy. The first investigations described include studies of radiation inducible gene therapy. In this paradigm, radio-inducible DNA sequences from the CarG elements of the Egr-1 promoter are cloned upstream of a cDNA encoding TNFα. The therapeutic gene (TNFα) is induced by radiation within the tumor microenvironment. In the second paradigm, genetically engineered herpes simplex virus (HSV-1) is induced by ionizing radiation to proliferate within the tumor volume. These modifications of radiotherapy and gene therapy may enhance the efficacy of both treatments. [ABSTRACT FROM AUTHOR]

Angiostatin is a cleavage product of plasminogen that has anti-angiogenic properties. We investigated whether the effects of angiostatin on endothelial cells are mediated by ceramide, a lipid implicated in endothelial cell signaling. Our results demonstrate that angiostatin produces a transient increase in ceramide that correlates with actin stress fiber reorganization, detachment and death. DNA array expression analysis performed on ceramide-treated human endothelial cells demonstrated induction of certain genes involved in cytoskeleton organization. Specifically, we report that treatment with angiostatin or ceramide results in the activation of RhoA, an important effector of cytoskeletal structure. We also show that treatment of endothelial cells with the antioxidant N-acetylcysteine abrogates morphological changes and cytotoxic effects of treatment with angiostatin or ceramide. These findings support a model in which angiostatin induces a transient rise in ceramide, RhoA activation and free radical production. [ABSTRACT FROM AUTHOR]

Evaluates whether endostatin, an antiangiogenic cleavage fragment of collagen XVIII, enhances the antitumor effects of ionizing radiation (IR). Injection of endostatin to coincide with fractionated radiotherapy; Tumor regression observed after combined treatment with endostatin and IR.