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Jewett A.,University of California at Los Angeles | Man Y.-G.,Diagnostic and Translational Research Center | Man Y.-G.,Jilin University | Cacalano N.,University of California at Los Angeles | And 2 more authors.
Journal of Immunotoxicology | Year: 2014

Evidence has previously been demonstrated for the role of NK cells in specific elimination of healthy stem cells (e.g. hMSC, hDPSC, hESC, hiPSC) as well as cancer stem cells, but not their differentiated counterparts. There is also a stage-wise susceptibility to NK cell-mediated cyto-toxicity in tumors, in which case the poorly-differentiated tumors are lysed much more than moderately-differentiated tumors. Well-differentiated tumors were lysed the least compared to either moderately- or poorly-differentiated tumors. It has also been reported that inhibition of differentiation or reversion of cells to a less-differentiated stage by blocking NF-κB or by gene deletion of COX2 significantly augmented NK cell cytotoxicity against both transformed and healthy cells. Additionally, the cytotoxic function of NK cells was severely inhibited against stem cells when they were cultured in the presence of monocytes. Therefore, it is proposed that CD16+CD56dimCD69- NK cells were important for the selection of stem cells, whereas the CD16dim/-CD56dim/+CD69+ anergized NK cells were important for differentiation and eventual regeneration of the tissues and the resolution of inflammation, thus potentially serving as regulatory NK (NKreg) cells. The concept of 'split anergy' in NK cells and the generation of NKreg cells with regard to contributions to cell differentiation, tissue repair and regeneration and in tumor resistance are discussed in this review. © 2014 Informa Healthcare USA, Inc.


Song G.,Peking University | Ren J.,Peking University | Stojadinovic A.,The Surgical Center | Stojadinovic A.,Uniformed Services University of the Health Sciences | And 5 more authors.
Cancer Epidemiology | Year: 2012

Our previous studies have led to a novel hypothesis that tumor metastasis is triggered by aberrant lymphocyte infiltration that disrupts intercellular junctions and surface adhesion molecules and causes dissociation of tumor cells from the primary tumor core, allowing lymphocytes to conjoin with dissociated tumor cells and physically 'drag' them to different tissue sites. Our hypothesis is supported by morphological and immunohistochemical data from multiple types of human cancer. This hypothesis challenges the traditional belief that the physical conjunction between tumor cells and lymphocytes would lead to degeneration of the tumor cells. To validate our hypothesis, H&E and immunostained sections were examined under high magnification to identify potential signs of degeneration-related changes. Our study revealed that >60% of isolated tumor cells overlying focal capsule disruptions, or within the stroma and vascular structures, were physically conjoined with lymphocytes to form tumor cell-lymphocyte chimeras (TLCs). Approximately 90% of the tumor cell partners of TLCs were morphologically indistinguishable from their counterparts within the tumor core. In addition, one third of the tumor cells of TLCs expressed high levels of cell proliferation specific proteins, or were undergoing mitosis. Our study also revealed that a subset of dilated lymphatic ducts or blood vessels at the site of focal capsule disruptions harbored variable numbers of tumor cells, and the wall of these structures was in direct physical continuity with the myoepithelial cell layer. Our study suggests that the onset of tumor metastasis may occur in two forms: (1) lymphocyte-mediated shuttling that allows lymphocytes to physically 'drag' tumor cells to different sites, and (2) tumor progenitor-mediated angiogenesis that allows tumor cells to directly enter the vascular structures. © 2011 Elsevier Ltd.


Man Y.-G.,Armed Forces Institute of Pathology and American Registry of Pathology | Man Y.-G.,Diagnostic and Translational Research Center | Izadjoo M.,Armed Forces Institute of Pathology and American Registry of Pathology | Izadjoo M.,Diagnostic and Translational Research Center | And 2 more authors.
Journal of Cancer | Year: 2011

The human breast lobular and ductal structures and the derived tumors from these structures differ substantial in their morphology, microenvironment, biological presen-tation, functions, and clinical prognosis. Based on these differences, we have proposed that pre-invasive lobular tumors may progress to invasive lesions through "in situ ma-lignant transformation", in which the entire myoepithelial cell layer within a given lobule or lobular clusters undergoes extensive degeneration and disruptions, which allows the entire epithelial cell population associated with these myoepithelial cell layers directly invade the stroma or vascular structures. In contrast, pre-invasive ductal tumors may invade the stroma or vascular structures through "progenitor-mediated cell budding", in which focal myoepithelial cell degeneration-induced aberrant leukocyte infiltration causes focal disruptions in the tumor capsules, which selectively favor monoclonal pro-liferation of the overlying tumor stem cells or a biologically more aggressive cell clone. Our current study attempted to provide more direct morphological and immunohisto-chemical data that are consistent with our hypotheses. © Ivyspring International Publisher.


Man Y.-G.,Diagnostic and Translational Research Center | Man Y.-G.,Jilin University | Stojadinovic A.,Uniformed Services University of the Health Sciences | Mason J.,Veterans Affair Medical Center | And 8 more authors.
Journal of Cancer | Year: 2013

It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destructions of the tumor cells, reduction of the tumor burden, and improved clinical prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. This mini-review presents several existing hypotheses and models that favor the promoting impact of tumor-infiltrating immune cells on tumor invasion and metastasis, and also analyzes their strength and weakness. ©Ivyspring International Publisher.


Jiang B.,Nanjing University | Mason J.,Veterans Affair Medical Center | Jewett A.,Jonson Comprehensive Cancer Center | Qian J.,Nanjing University | And 5 more authors.
International Journal of Biological Sciences | Year: 2012

Background: Colorectal carcinogenesis is believed to be a multi-stage process that originates with a localized adenoma, which linearly progresses to an intra-mucosal carcinoma, to an invasive lesion, and finally to metastatic cancer. This progression model is supported by tissue culture and animal model studies, but it is difficult to reconcile with several well-established observations, principally among these are that up to 25% of early stage (Stage I/II), node-negative colorectal cancer (CRC) develop distant metastasis, and that circulating CRC cells are undetectable in peripheral blood samples of up to 50% of patients with confirmed metastasis, but more than 30% of patients with no detectable metastasis exhibit such cells. The mechanism responsible for this diverse behavior is unknown, and there are no effective means to identify patients with pending, or who are at high risk for, developing metastatic CRC. Novel findings: Our previous studies of human breast and prostate cancer have shown that cancer invasion arises from the convergence of a tissue injury, the innate immune response to that injury, and the presence of tumor stem cells within tumor capsules at the site of the injury. Focal degeneration of a capsule due to age or disease attracts lymphocyte infiltration that degrades the degenerating capsules resulting in the formation of a focal disruption in the capsule, which selectively favors proliferating or "budding" of the underlying tumor stem cells. Our recent studies suggest that lymphocyte infiltration also triggers metastasis by disrupting the intercellular junctions and surface adhesion molecules within the proliferating cell buds causing their dissociation. Then, lymphocytes and tumor cells are conjoined through membrane fusion to form tumor-lymphocyte chimeras (TLCs) that allows the tumor stem cell to avail itself of the lymphocyte's natural ability to migrate and breach cell barriers in order to intravasate and to travel to distant organs. Our most recent studies of human CRC have detected nearly identical focal capsule disruptions, lymphocyte infiltration, budding cells, and the formation of TLCs. Our studies have further shown that age- and type-matched node-positive and -negative CRC have a significantly different morphological and immunohistochemical profile and that the majority of lymphatic ducts with disseminated cells are located within the mucosa adjacent to morphologically normal appearing epithelial structures that express a stem cell-related marker. New hypothesis: Based on these findings and the growth patterns of budding cells revealed by double immunohistochemistry, we further hypothesize that metastatic spread is an early event of carcinogenesis and that budding cells overlying focal capsule disruptions represent invasion- and metastasis-initiating cells that follow one of four pathways to progress: (1) to undergo extensive in situ proliferation leading to the formation of tumor nests that subsequently invade the submucosa, (2) to migrate with associated lymphocytes functioning as "seeds" to grow in new sites, (3) to migrate and intravasate into pre-existing vascular structures by forming TLCs, or (4) to intravasate into vascular structures that are generated by the budding cells themselves. We also propose that only node-positive cases harbor stem cells with the potential for multi-lineage differentiation and unique surface markers that permit intravasation. © Ivyspring International Publisher.


Jiang B.,Nanjing University of Traditional Chinese Medicine | Mason J.,Veterans Affairs Medical Center | Jewett A.,Jonsson Comprehensive Cancer Center | Liu M.-L.,Veterans Affairs Medical Center | And 8 more authors.
International Journal of Medical Sciences | Year: 2013

Background: Our previous studies of human breast and prostate cancer have shown that aberrant immune cell infiltration is associated with focal tumor capsule disruption and tumor cell budding that facilitate invasion and metastasis. Our current study attempted to determine whether aberrant immune cell infiltration would have similar impact on colorectal cancer (CRC). Materials and Methods: Tissue sections from 100 patients with primary CRC were assessed for the frequencies of focal basement membrane (BM) disruption, muscularis mucosa (MM) fragmentation, and tumor cell dissemination in epithelial structures adjacent and distal to infiltrating lymphoid aggregates using a panel of biomarkers and quantitative digital imaging. Results: Our study revealed: (1) epithelial structures adjacent to lymphoid follicles or aggregates had a significantly higher (p<0.001) frequency of focally disrupted BM, dissociated epithelial cells in the stroma, disseminated epithelial cells within lymphatic ducts or blood vessels, and fragmented MM than their distal counterparts, (2) a majority of dissociated epithelial cells within the stroma or vascular structures were immediately subjacent to or physically associated with infiltrating immune cells, (3) the junctions of pre-invasive and invasive lesions were almost exclusively located at sites adjacent to lymphoid follicles or aggregates, (4) infiltrating immune cells were preferentially associated with epithelial capsules that show distinct degenerative alterations, and (5) infiltrating immune cells appeared to facilitate tumor stem cell proliferation, budding, and dissemination. Conclusions: Aberrant immune cell infiltration may have the same destructive impact on the capsule of all epithelium-derived tumors. This, in turn, may selectively favor the proliferation of tumor stem or progenitor cells overlying these focal disruptions. These proliferating epithelial tumor cells subsequently disseminate from the focal disruption leading to tumor invasion and metastasis. © Ivyspring International Publisher.


Antonic V.,Foundation Medicine | Antonic V.,Diagnostic and Translational Research Center | Zhang B.,Foundation Medicine | Zhang B.,Diagnostic and Translational Research Center | And 5 more authors.
Infection and Drug Resistance | Year: 2013

Staphyloxanthin is a virulence factor which protects Staphylococcus aureus in stress conditions. We isolated two pigment variants of S. aureus and one strain of Pseudomonas aeruginosa from a single wound infection. S. aureus variants displayed white and yellow colony phenotypes. The sequence of the operons for staphyloxanthin synthesis indicated that coding and promoter regions were identical between the two pigment variants. Quorum sensing controls pigment synthesis in some bacteria. It is also shown that P. aeruginosa quorum-sensing molecules affect S. aureus transcription. We explored whether the co-infecting P. aeruginosa can affect pigment production in the white S. aureus variant. In co-culture experiments between the white variants and a selected number of Gram-positive and Gram-negative bacteria, only P. aeruginosa induced pigment production in the white variant. Gene expression analysis of the white variant did not indicate upregulation of the crtM and other genes known to be involved in pigment production (sigB, sarA, farnesyl pyrophosphate synthase gene [FPP-synthase], hfq). In contrast, transcription of the catalase gene was significantly upregulated after co-culture. P. aeruginosa-induced pigment synthesis and catalase upregulation correlated with increased resistance to polymyxin B, hydrogen peroxide, and the intracellular environment of macrophages. Our data indicate the presence of silent but functional staphyloxanthin synthesis machinery in a white phenotypic variant of S. aureus which is activated by a co-infecting P. aeruginosa via inter-species communication. Another S. aureus virulence factor, catalase is also induced by this co-infecting bacterium. The resulting phenotypic changes are directly correlated with resistance of the white variant to stressful conditions. © 2013 Antonic et al.


Man Y.-G.,Diagnostic and Translational Research Center | Fu S.W.,George Washington University | Liu A.J.,Beijing 301 Hospital | Stojadinovic A.,U.S. Army | And 3 more authors.
Cancer Genomics and Proteomics | Year: 2011

Our recent studies have suggested that prostate tumor invasion is triggered by autoimmunoreactions induced focal basal cell layer disruptions (FBCLD) that selectively favor monoclonal proliferation of the overlying progenitors or of a biologically more aggressive cell clone. As circulating chromogranin-A (CgA) levels are found to correlate with tumor progression and the status of hormone refractoriness, our current study attempted to assess whether CgA-positive cells would be preferentially distributed in epithelial structures with FBCLD. Paraffin-embedded specimens from 50 patients with organ-confined prostate cancer were subjected to double immunohistochemical analysis with monoclonal antibodies to basal cells and CgA. From each case, 3-5 randomly selected fields were digitally photographed and the photos were magnified 400% and the numbers of CgA-positive cells in epithelial structures with non-disrupted, focally disrupted, and lost basal cell layer were separately counted. The averaged number of cell for each category was statistically compared with the Pearson's Chi-square test. In addition, morphologically similar structures with and without CgA-positive cell clusters were microdissected from four selected cases and subjected to a comparison of differential micro-RNA expression levels. Our study revealed that, although isolated CgA-positive cells were seen in both the basal cell layer and the luminal cell population in all cases, only 8 cases (16%) harbored large clusters of CgA-positive cells that were concentrated in a given area, in which all or nearly all cells appeared to share a similar morphological and immunohistochemical profile. Microdissected epithelial structures with CgA-positive cell clusters exhibited a more than 5- and 7-fold lower expression of miR-146a and miR-146b-5p than their CgA-negative counterparts. As focal basal cell layer disruptions and the reduction or loss of miR-146a and miR-146b-5p has been documented to correlate with prostate tumor invasion and hormone refractoriness, our findings suggest that aberrant CgA expression in epithelial structures with FBCLD may represent an early sign of these events.


Wang J.,Georgetown University | Zuo Y.,Georgetown University | Zuo Y.,Virginia Polytechnic Institute and State University | Liu L.,Beijing Academy of Agriculture and Forestry Sciences | And 3 more authors.
Circulation: Cardiovascular Genetics | Year: 2014

Background-Prediction of functional modules is indispensable for detecting protein deregulation in human complex diseases such as cancer. Bayesian network is one of the most commonly used models to integrate heterogeneous data from multiple sources such as protein domain, interactome, functional annotation, genome-wide gene expression, and the literature. Methods and Results-In this article, we present a Bayesian network classifier that is customized to (1) increase the ability to integrate diverse information from different sources, (2) effectively predict protein-protein interactions, (3) infer aberrant networks with scale-free and small-world properties, and (4) group molecules into functional modules or pathways based on the primary function and biological features. Application of this model in discovering protein biomarkers of hepatocellular carcinoma leads to the identification of functional modules that provide insights into the mechanism of the development and progression of hepatocellular carcinoma. These functional modules include cell cycle deregulation, increased angiogenesis (eg, vascular endothelial growth factor, blood vessel morphogenesis), oxidative metabolic alterations, and aberrant activation of signaling pathways involved in cellular proliferation, survival, and differentiation. Conclusions-The discoveries and conclusions derived from our customized Bayesian network classifier are consistent with previously published results. The proposed approach for determining Bayesian network structure facilitates the integration of heterogeneous data from multiple sources to elucidate the mechanisms of complex diseases. © 2014 American Heart Association, Inc.


PubMed | Diagnostic and Translational Research Center
Type: Journal Article | Journal: Cancer genomics & proteomics | Year: 2011

Our recent studies have suggested that prostate tumor invasion is triggered by autoimmunoreactions induced focal basal cell layer disruptions (FBCLD) that selectively favor monoclonal proliferation of the overlying progenitors or of a biologically more aggressive cell clone. As circulating chromogranin-A (CgA) levels are found to correlate with tumor progression and the status of hormone refractoriness, our current study attempted to assess whether CgA-positive cells would be preferentially distributed in epithelial structures with FBCLD. Paraffin-embedded specimens from 50 patients with organ-confined prostate cancer were subjected to double immunohistochemical analysis with monoclonal antibodies to basal cells and CgA. From each case, 3-5 randomly selected fields were digitally photographed and the photos were magnified 400% and the numbers of CgA-positive cells in epithelial structures with non-disrupted, focally disrupted, and lost basal cell layer were separately counted. The averaged number of cell for each category was statistically compared with the Pearsons Chi-square test. In addition, morphologically similar structures with and without CgA-positive cell clusters were microdissected from four selected cases and subjected to a comparison of differential micro-RNA expression levels. Our study revealed that, although isolated CgA-positive cells were seen in both the basal cell layer and the luminal cell population in all cases, only 8 cases (16%) harbored large clusters of CgA-positive cells that were concentrated in a given area, in which all or nearly all cells appeared to share a similar morphological and immunohistochemical profile. Microdissected epithelial structures with CgA-positive cell clusters exhibited a more than 5- and 7-fold lower expression of miR-146a and miR-146b-5p than their CgA-negative counterparts. As focal basal cell layer disruptions and the reduction or loss of miR-146a and miR-146b-5p has been documented to correlate with prostate tumor invasion and hormone refractoriness, our findings suggest that aberrant CgA expression in epithelial structures with FBCLD may represent an early sign of these events.

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