Transglutaminase 2 Overexpression in Tumor Stroma Identifies Invasive Ductal Carcinomas of Breast at High Risk of Recurrence

Assi, Jasmeet; Srivastava, Gunjan; Matta, Ajay; Chang, Martin C.; Walfish, Paul G.; Ralhan, Ranju

doi:10.1371/journal.pone.0074437

Cited by 40 publications

(30 citation statements)

References 44 publications

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“…SPON2 and its translational product, Spondin-2, have been found to be up-regulated in many types of cancer [37][38][39], and its expression is a prognostic factor in prostate and colorectal cancer [40,41]. In breast cancer, expression of TGM2 in tumor stroma is an independent risk factor for breast cancer patients at high risk of recurrence [42]. In AML, TGM2 was found up-regulated particularly in relapsed patients and correlated with increased expression of numerous adhesion proteins and many apoptosis regulating proteins [43].…”

Section: Discussionmentioning

confidence: 99%

Untitled

2017

Oncotarget

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The genetic heterogeneity of acute myeloid leukemia (AML) and the variable responses of individual patients to therapy suggest that different AML genotypes may influence the bone marrow (BM) microenvironment in different ways. We performed gene expression profiling of bone marrow mesenchymal stromal cells (BM-MSC) isolated from normal C57BL/6 mice or mice inoculated with syngeneic murine leukemia cells carrying different human AML genotypes, developed in mice with Trp53 wild-type or null genetic backgrounds. We identified a set of genes whose expression in BM-MSC was modulated by all four AML genotypes tested. In addition, there were sets of differentially-expressed genes in AML-exposed BM-MSC that were unique to the particular AML genotype or Trp53 status. Our findings support the hypothesis that leukemia cells alter the transcriptome of surrounding BM stromal cells, in both common and genotype-specific ways. These changes are likely to be advantageous to AML cells, affecting disease progression and response to chemotherapy, and suggest opportunities for stroma-targeting therapy, including those based on AML genotype.

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Section: Discussionmentioning

confidence: 99%

Untitled

2017

Oncotarget

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“…Assi et al (20) reported that patients with stromal TG2 accumulation had significantly decreased disease-free survival (DFS; mean DFS, 110 months) compared with patients with low TG2 expression (mean DFS, 130 months). On the basis of these observations, it may be hypothesized that high TG2 expression levels correlate with poor clinical outcome in patients with breast cancer, which leads to a decreased sensitivity to TXT chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Silencing of TGM2 reverses epithelial to mesenchymal transition and modulates the chemosensitivity of breast cancer to docetaxel

Sun

Liu

2015

Experimental and Therapeutic Medicine

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Abstract. Epithelial to mesenchymal transition (EMT) plays a critical role in drug resistance. The aim of the present study was to further elucidate its role by examining the effect of tissue transglutaminase (TG2) on EMT and drug resistance in breast cancer. An antisense lentiviral (LV) short hairpin (sh)RNA construct specific to the TG2 gene (TGM2) was designed, synthesized and stably transfected into MDA-MB-231 cells to silence TGM2 by RNA interference (RNAi). The transfected cells expressed low levels of TG2 and constituted the RNAi (TGM2-shRNA) group. A control (NC) group was also established by transfecting MDA-MB-231 cells with scrambled shRNA. The expression levels of TG2, E-cadherin, vimentin and B-cell lymphoma (Bcl)-2 in the cells were examined via western blotting. The transfected MDA-MB-231 cells were divided into four groups, two of which were treated with doxetaxel (TXT): NC, RNAi, TXT and RNAi + TXT groups,. Cell proliferation was analyzed by MTT assay and cell apoptosis was detected by flow cytometry. An in vivo assay was also conducted, in which MDA-MB-231 cells transfected with scrambled shRNA or TGM2-shRNA were subcutaneously implanted into nude mice. After 2 weeks, TXT or vehicle was intraperitoneally administered at a dose of 10 mg/kg on day 1 of every week and tumor growth was monitored. Following the silencing of TGM2 in the MDA-MB-231 cells, the cells showed changes in morphology, indicating that an increased expression of TG2 was associated with a mesenchymal morphology. Transfection of the cells with TGM2-shRNA affected the expression of TG2, E-cadherin, vimentin and Bcl-2. In the MTT assay, the proliferation of MDA-MB-231 cells was significantly inhibited in the RNAi group compared with the control group (P<0.05), and the inhibitory effect increased in a time-dependent manner. Following treatment with TXT for 48 h, apoptosis was significantly promoted in the RNAi + TXT group compared with that in the other groups (P<0.05). Measurement of the tumors in the nude mice indicated that the combination of RNAi and TXT brought about a stronger antitumor effect than either treatment alone. These results suggest that the downregulation of TG2 reversed EMT and modulated the chemosensitivity of breast cancer to TXT. TG2 may be an important predictive and prognostic factor for the treatment efficacy of chemotherapy in patients with breast cancer.

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“…Interestingly, CD73 is expressed not only on MSC but also on tumor cells and Treg cells, suggesting that the adenosine found within TME can be derived from different sources, to further amplify the strong inhibitory effect derived from a single cell type [13,14,15]. Transglutaminase (TG)-II can be used to selectively identify MSC in immunohistochemistry and cytofluorimetry [16,17,18,19,20,21,22,23]; however, it is also expressed on tumor cells undergoing EMT. TG-II is involved in several processes that can regulate tumor cell proliferation and apoptosis [16,17,18,19,20,21].…”

Section: Msc Phenotypic and Functional Features Relevant In The Inmentioning

confidence: 99%

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

Poggi

Giuliani

2016

Vaccines

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The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC) activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT), a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

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Transglutaminase 2 Overexpression in Tumor Stroma Identifies Invasive Ductal Carcinomas of Breast at High Risk of Recurrence

Cited by 40 publications

References 44 publications

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Silencing of TGM2 reverses epithelial to mesenchymal transition and modulates the chemosensitivity of breast cancer to docetaxel

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

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