Angiopoietins Promote Ovarian Cancer Progression by Establishing a Procancer Microenvironment
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Despite decades of research, the survival rate of ovarian cancer patients is largely unchanged. Current chemotherapeutic drugs are effective only transiently because patients with advanced disease eventually develop resistance. Thus, there is a pressing need for identifying novel therapeutic targets in ovarian cancer. Mounting evidence suggests that angiopoietins (Angpts) may play an essential role in cancer progression; however, the expression profiles and biological effects of Angpts on ovarian cancer remain largely unknown. Here, we show that, compared with their normal counterparts, expressions of Angpt1, Angpt2, and Angpt4 are increased in ovarian cancer cells and tissues and that human ovarian cancer cells also express the Angpt receptor Tie-2-receptor tyrosine kinase. We show that increased expression of Angpt1, Angpt2, or Angpt4 promotes intraperitoneal growth of ovarian cancers and shortens survival of the experimental mice. We further show, for the first time, that Angpts promote accumulation of cancer-associated fibroblasts and tumor angiogenesis in the ovarian cancer microenvironment, as well as enhance ovarian cancer cell proliferation and invasion in vivo. In addition, we establish a novel function of Angpts in promoting proliferation and invasion and inducing Tie-2 and extracellular signal-regulated kinase 1/2 activation in ovarian cancer-associated fibroblasts. Taken together, these data suggest that the Angpt-Tie-2 functional axis is an important player in ovarian cancer progression and an attractive target for ovarian cancer therapy.Keywords:
Tumor progression
The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cells that make up the microenvironment to promote tumor growth and suppress endogenous defense systems, such as the immune and inflammatory response. We have previously demonstrated that stimulation of Tsp-1 in the tumor microenvironment (TME) potently inhibits tumor growth and progression. Here, we identify a novel tumor-mediated mechanism that represses the expression of Tsp-1 in the TME via secretion of the serine protease PRSS2. We demonstrate that PRSS2 represses Tsp-1, not via its enzymatic activity, but by binding to low-density lipoprotein receptor-related protein 1 (LRP1). These findings describe a hitherto undescribed activity for PRSS2 through binding to LRP1 and represent a potential therapeutic strategy to treat cancer by blocking the PRSS2-mediated repression of Tsp-1. Based on the ability of PRSS2 to reprogram the tumor microenvironment, this discovery could lead to the development of therapeutic agents that are indication agnostic.
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The tumor microenvironment has been widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer. In addition, nonmalignant cells in the tumor microenvironment play critical roles in all the stages of carcinogenesis by stimulating and facilitating uncontrolled cell proliferation.This study aims to explore the concept of the tumor microenvironment by conducting a critical review of previous studies on the topic. Materials and Methods: This review relies on evidence presented in previous studies related to the topic. The articles included in this review were obtained from different medical and health databases.The tumor microenvironment has received significant attention in the cancer literature, with a particular focus on its role in tumor development and progression. Previous studies have identified various components of the tumor microenvironment that influence malignant behavior and progression. In addition to malignant cells, adipocytes, fibroblasts, tumor vasculature, lymphocytes, dendritic cells, and cancer-associated fibroblasts are present in the tumor microenvironment. Each of these cell types has unique immunological capabilities that determine whether the tumor will survive and affect neighboring cells.The tumor microenvironment harbors cancer stem cells and other molecules that contribute to tumor development and progression. Consequently, targeting and manipulating the cells and factors in the tumor microenvironment during cancer treatment can help control malignancies and achieve positive health outcomes.
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Thermal ablation (TA), including radiofrequency ablation (RFA) and microwave ablation (MWA), has become the main treatment for early-stage hepatocellular carcinoma (HCC) due to advantages such as safety and minimal invasiveness. However, HCC is prone to local recurrence, with more aggressive malignancies after TA closely related to TA-induced changes in epithelial-mesenchymal transition (EMT) and remodeling of the tumor microenvironment (TME). According to many studies, various components of the TME undergo complex changes after TA, such as the recruitment of innate and adaptive immune cells, the release of tumor-associated antigens (TAAs) and various cytokines, the formation of a hypoxic microenvironment, and tumor angiogenesis. Changes in the TME after TA can partly enhance the anti-tumor immune response; however, this response is weak to kill the tumor completely. Certain components of the TME can induce an immunosuppressive microenvironment through complex interactions, leading to tumor recurrence and progression. How the TME is remodeled after TA and the mechanism by which the TME promotes HCC recurrence and progression are unclear. Thus, in this review, we focused on these issues to highlight potentially effective strategies for reducing and preventing the recurrence and progression of HCC after TA.
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Abstract Although it is well recognized that the tumor microenvironment plays a key role in regulating tumor progression, the mechanisms through which this occurs need to be defined. Current international research activities toward defining the role of the tumor microenvironment in cancer progression were the subject of the first Tianjin Forum on Tumor Microenvironment held at Nankai University in Tianjin, China, July 2 to 4, 2010. The importance of variety of processes, such as inflammation and angiogenesis, in the role of tumor progression was described for multiple tumor types including breast, prostate, and hepatic cancers, as well as the process of bone metastasis. Identification of novel signaling pathways that impact both angiogenesis and bone remodeling were presented. Several themes emerged from this meeting, such as: (i) tumor cells modify the microenvironment to enhance their own survival and progression; (ii) targeting host factors, in addition to targeting tumor cells, will have important therapeutic effects; and (iii) host cells distribution within the tumor has both prognostic and therapeutic significance. Several priorities for future research were defined including use of a systems biology approach to define the role of host factors in tumor progression, to define the importance of targeting both arms of the bone remodeling process for therapy of bone metastasis, and to determine how different cell subsets contribute to microenvironment-mediated regulation of tumor progression. Cancer Res; 71(2); 310–3. ©2011 AACR.
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Distinct tumor microenvironment forms in each progression step of cancer and has diverse capacities to induce both adverse and beneficial consequences for tumorigenesis. It is now known that immune cells can be activated to favor tumor growth and progression, most probably influenced by the tumor microenvironment. Tumor-associated macrophages and tumor-associated neutrophils can exert protumoral functions, enhancing tumor cell invasion and metastasis, angiogenesis, and extracellular matrix remodeling, while inhibiting the antitumoral immune surveillance. Considering that neutrophils in inflammatory environments recruit macrophages and that recruited macrophages affect neutrophil functions, there may be various degrees of interaction between tumor-associated macrophages and tumor-associated neutrophils. Platelets also play an important role in the recruitment and regulation of monocytic and granulocytic cells in the tumor tissues, suggesting that platelet function may be essential for generation of tumor-associated macrophages and tumor-associated neutrophils. In this review, we will explore the biology of tumor-associated macrophages and tumor-associated neutrophils and their possible interactions in the tumor microenvironment. Special attention will be given to the recruitment and activation of these tumor-associated cells and to the roles they play in maintenance of the tumor microenvironment and progression of tumors.
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It is now widely accepted that the development and progression of a tumor toward the malignant phenotype is highly dependent on interactions between tumor cells and the tumor microenvironment. Different components of the tumor microenvironment may have stimulatory or inhibitory effects on tumor progression by regulating the gene expression repertoire in tumor cells and stromal cells. This review analyzes novel research findings on breast cancer progression, discussing acquisition of the metastatic phenotype in breast disease in relation to different aspects of cross-talk among components of the tumor microenvironment. Knowledge of the interaction of all of these factors would contribute to elucidating the mechanisms that disrupt regulatory/signaling cascades and downstream effects in breast cancer.
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<div>Abstract<p>Although it is well recognized that the tumor microenvironment plays a key role in regulating tumor progression, the mechanisms through which this occurs need to be defined. Current international research activities toward defining the role of the tumor microenvironment in cancer progression were the subject of the first Tianjin Forum on Tumor Microenvironment held at Nankai University in Tianjin, China, July 2 to 4, 2010. The importance of variety of processes, such as inflammation and angiogenesis, in the role of tumor progression was described for multiple tumor types including breast, prostate, and hepatic cancers, as well as the process of bone metastasis. Identification of novel signaling pathways that impact both angiogenesis and bone remodeling were presented. Several themes emerged from this meeting, such as: (i) tumor cells modify the microenvironment to enhance their own survival and progression; (ii) targeting host factors, in addition to targeting tumor cells, will have important therapeutic effects; and (iii) host cells distribution within the tumor has both prognostic and therapeutic significance. Several priorities for future research were defined including use of a systems biology approach to define the role of host factors in tumor progression, to define the importance of targeting both arms of the bone remodeling process for therapy of bone metastasis, and to determine how different cell subsets contribute to microenvironment-mediated regulation of tumor progression. <i>Cancer Res; 71(2); 310–3. ©2011 AACR</i>.</p></div>
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