TGF-ß signaling, tumor microenvironment and tumor progression: the butterfly effect

Joshi, Amit; Cao, Deliang

doi:10.2741/3614

Cited by 73 publications

(73 citation statements)

References 121 publications

(191 reference statements)

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“…In tumor tissue, TGF-b1 has a bimodal function and can inhibit or support tumor growth depending on the tumor cell type and the tumor growth phase. 39 MDA-MB-231 cells belong to those tumor cells, which are resistant to the growth inhibition of TGF-b1, although they are responsive with respect to TGF-b1-induced gene expression. 40 This supports the role of autocrine TGF-b1 in tumor progression in this cell type.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Wottawa

Leisering

Ahlen

et al. 2012

Intl Journal of Cancer

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The prolyl-4-hydroxylase domain 1-3 (PHD1-3) enzymes are regulating the protein stability of the a-subunit of the hypoxiainducible factor-1 (HIF-1), which mediates oxygen-dependent gene expression. PHD2 is the main isoform regulating HIF-1a hydroxylation and thus stability in normoxia. In human cancers, HIF-1a is overexpressed as a result of intratumoral hypoxia which in turn promotes tumor progression. The role of PHD2 for tumor progression is in contrast far from being thoroughly understood. Therefore, we established PHD2 knockdown clones of MDA-MB-231 breast cancer cells and analyzed their tumorforming potential in a SCID mouse model. Tumor progression was significantly impaired in the PHD2 knockdown MDA-MB-231 cells, which could be partially rescued by re-establishing PHD2 expression. In a RNA profile screen, we identified the secreted phosphoprotein 1 (SPP1) as one target, which is differentially regulated as a consequence of the PHD2 knockdown. Knockdown of PHD2 drastically reduced the SPP1 expression in MDA-MB-231 cells. A correlation of SPP1 and PHD2 expression was additionally verified in 294 invasive breast cancer biopsies. In subsequent analyses, we identified that PHD2 alters the processing of transforming growth factor (TGF)-b1, which is highly involved in SPP1 expression. The altered processing capacity was associated with a dislocation of the pro-protein convertase furin. Thus, our data demonstrate that in MDA-MB-231 cells PHD2 might affect tumor-relevant TGF-b1 target gene expression by altering the TGF-b1 processing capacity.

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Section: Discussionmentioning

confidence: 99%

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Wottawa

Leisering

Ahlen

et al. 2012

Intl Journal of Cancer

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“…The expression of TGF-β1 can be detected in almost all types of tumors and exists at an upregulated level in cancer cells, allowing it to inhibit normal cell proliferation yet enhance the growth of tumor cells (23). During the early stage of tumorigenesis, TGF-β1 may be an inhibitor of tumor cells through the suppression of many cell functions; however, following the development of malignance, it promotes tumor cell proliferation (24). TGF-β1 exists within cells as a non-active complex that must be activated in order to exert a biological effect on its major downstream signaling molecule, Smad (25).…”

Section: Discussionmentioning

confidence: 99%

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

Zhang

et al. 2012

Oncology Letters

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Abstract. Human choriocarcinoma is one of the most aggressive malignant tumors characterized by early hematogenous spread to lung and brain tissues, and may be a cause of death in patients. Choriocarcinoma may occur following pregnancy and during implantation; however, trophoblastic invasion in human pregnancy is tightly regulated. The transforming growth factor-beta 1 (TGF-β1) has been suggested to play a role in controlling this process. In this study, we investigated the impact of TGF-β1 on invasion, as well as its sites of action in the TGF-β1/Smad pathway using a JEG-3 choriocarcinoma cell line. Following the treatment of cells with different doses of TGF-β1, cell invasion was observed. We also detected the expression of TGF-β receptor type I (TβR I) and TGF-β receptor type II (TβR II), Smad4, matrix metalloprotease (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in JEG-3 cells. Our data demonstrated that TGF-β1 promoted the invasive capability of JEG-3 cells depending on the downregulation of TβR I, TβR II, Smad4 and the upregulation of MMP-9 and TIMP-1. These observations suggest that TGF-β1 may play a critical role in the initiation of the trophoblastic invasion process. IntroductionA successful human pregnancy requires embryonic trophocytes to invade into the womb and adhere to the endometrium; however, this kind of invasion is strictly regulated temporospatially (1). The deregulation of the invasion process may cause a series of pregnancy-related diseases, such as hydatidiform mole and invasive mole; however, excessive invasion of trophocytes is significantly associated with the formation of placental choriocarcinoma (2). In this process, one critical step of choriocarcinoma invasion and metastasis is the degradation of the extracellular matrix (ECM), in which the MMP-9/TIMP-1 ratio plays a significant role (3,4).The main treatment for choriocarcinoma is 5-fluorouracil, which has a very good therapeutic efficacy; however, it may also cause toxic reactions, side effects and drug resistance (5). Since conventional treatments including surgery and chemotherapy often fail, it is necessary to explore the metastasis mechanisms of proliferation and invasiveness, and find a new target for drug therapy.TGF-β belongs to a growth factor super-family which consists of a highly evolutionary conserved group of secreted cytokines (6). The TGF-β family consists of TGF-β, activins, bone morphogenetic proteins (BMPs), nodals, inhibins and antimullerian hormone (AMH). TGF-β1 is the prototypic family member and is secreted as an inactive latent precursor (7,8). It plays a significant role in the control of growth and development, including the regulation of cell proliferation and differentiation, the promotion of ECM formation and suppression of the immune response (9). TGF-β1 exerts its cellular effects through TβR I, TβR II and the Smad transcription factors, which have pivotal roles in intracellular signaling (7,10). Moreover, Smad4 is an essential factor in TGF-β signaling and is a frequently mutated tumor ...

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“…As a tumor suppressor, it has antiproliferative effects in the early stages of tumorigenesis, but tumor cells in later stages evade this effect and progress in response to TGF-b ( Fig. 1) ( Joshi and Cao 2010;Band and Laiho 2011;Inman 2011;Meulmeester and Ten Dijke 2011;Zu and others 2012). TGF-b, TbRII (the receptor required for TGF-b signaling), and phospho-Smad2 expression are associated with earlier age of onset and aggressive tumor characteristics (Figueroa and others 2010).…”

Section: Transforming Growth Factor-bmentioning

confidence: 99%

The Role of Cytokines in Breast Cancer Development and Progression

Esquivel-Velázquez

Ostoa‐Saloma

Palacios-Arreola

et al. 2015

Journal of Interferon & Cytokine Research

422

363

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Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancerrelated disorders.

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TGF-ß signaling, tumor microenvironment and tumor progression: the butterfly effect

Cited by 73 publications

References 121 publications

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

The Role of Cytokines in Breast Cancer Development and Progression

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