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Hypoxia and TGF-β Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment  [PDF]
Lauren K. Dunn, Khalid S. Mohammad, Pierrick G. J. Fournier, C. Ryan McKenna, Holly W. Davis, Maria Niewolna, Xiang Hong Peng, John M. Chirgwin, Theresa A. Guise
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006896
Abstract: Background Most patients with advanced breast cancer develop bone metastases, which cause pain, hypercalcemia, fractures, nerve compression and paralysis. Chemotherapy causes further bone loss, and bone-specific treatments are only palliative. Multiple tumor-secreted factors act on the bone microenvironment to drive a feed-forward cycle of tumor growth. Effective treatment requires inhibiting upstream regulators of groups of prometastatic factors. Two central regulators are hypoxia and transforming growth factor (TGF)- β. We asked whether hypoxia (via HIF-1α) and TGF-β signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model. Methodology/Principal Findings We analyzed interactions between HIF-1α and TGF-β pathways in MDA-MB-231 breast cancer cells. Only vascular endothelial growth factor (VEGF) and the CXC chemokine receptor 4 (CXCR4), of 16 genes tested, were additively increased by both TGF-β and hypoxia, with effects on the proximal promoters. We inhibited HIF-1α and TGF-β pathways in tumor cells by shRNA and dominant negative receptor approaches. Inhibition of either pathway decreased bone metastasis, with no further effect of double blockade. We tested pharmacologic inhibitors of the pathways, which target both the tumor and the bone microenvironment. Unlike molecular blockade, combined drug treatment decreased bone metastases more than either alone, with effects on bone to decrease osteoclastic bone resorption and increase osteoblast activity, in addition to actions on tumor cells. Conclusions/Significance Hypoxia and TGF-β signaling in parallel drive tumor bone metastases and regulate a common set of tumor genes. In contrast, small molecule inhibitors, by acting on both tumor cells and the bone microenvironment, additively decrease tumor burden, while improving skeletal quality. Our studies suggest that inhibitors of HIF-1α and TGF-β may improve treatment of bone metastases and increase survival.
PC-3 prostate carcinoma cells release signal substances that influence the migratory activity of cells in the tumor's microenvironment
Melanie J Voss, Bernd Niggemann, Kurt S Z?nker, Frank Entschladen
Cell Communication and Signaling , 2010, DOI: 10.1186/1478-811x-8-17
Abstract: PC-3 cells express several cytokines and growth factors including vascular endothelial growth factors, fibroblast growth factors, interleukins and neurotrophic factors. SH-SY5Y cells are impaired in their migratory activity by PC-3 cell culture supernatant, but orientate chemotactically towards the source. Neutrophil granulocytes increase their locomotory activity only in response to cell culture supernantant of hypoxic but not of normoxic PC-3 cells. In contrast, cytotoxic T lymphocytes do not change their migratory activity in response to either culture supernatant, but increase their cytotoxicity, whereas supernatant of normoxic PC-3 cells leads to a stronger increase than that of hypoxic PC-3 cells.PC-3 cells release several signal substances that influence the behavior of the cells in the tumor's microenvironment, whereas no clear pattern towards proinflammatory or immunosuppressive conditions can be seen.Today's understanding of the biology of tumors increasingly shows a crucial role of the microenvironment in the tumors' growth and the course of the cancer disease. This environmental interactions concern the development of new blood vessels in tumors (called neoangiogenesis), which was one of the first tumor-stroma interactions described in 1971 by Judah Folkman and colleagues [1], as well as similarly the development of new lymph vessels (lymphangiogenesis) [2], and the innervation of tumors, which we have termed neoneurogenesis [3,4]. Because of strong similarities to tissue growth and regeneration, tumors are regarded as wounds that do not heal [5]. A further argument for a comparison of tumors and wounds is the presence of cells of the immune system as well as fibroblasts infiltrating tumors being redolent of inflammatory conditions. Such parallels have already been observed by Virchow back in 1863, and this hypothesis of a non-healing wound has been seized and refined by Balkwill and Mantovani [6]. An inflammatory milieu is regarded as beneficial for a t
mRNA-Seq of Single Prostate Cancer Circulating Tumor Cells Reveals Recapitulation of Gene Expression and Pathways Found in Prostate Cancer  [PDF]
Gordon M. Cann,Zulfiqar G. Gulzar,Samantha Cooper,Robin Li,Shujun Luo,Mai Tat,Sarah Stuart,Gary Schroth,Sandhya Srinivas,Mostafa Ronaghi,James D. Brooks,AmirAli H. Talasaz
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049144
Abstract: Circulating tumor cells (CTC) mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.
Tumor Microenvironment in the Brain  [PDF]
Mihaela Lorger
Cancers , 2012, DOI: 10.3390/cancers4010218
Abstract: In addition to malignant cancer cells, tumors contain a variety of different stromal cells that constitute the tumor microenvironment. Some of these cell types provide crucial support for tumor growth, while others have been suggested to actually inhibit tumor progression. The composition of tumor microenvironment varies depending on the tumor site. The brain in particular consists of numerous specialized cell types such as microglia, astrocytes, and brain endothelial cells. In addition to these brain-resident cells, primary and metastatic brain tumors have also been shown to be infiltrated by different populations of bone marrow-derived cells. The role of different cell types that constitute tumor microenvironment in the progression of brain malignancies is only poorly understood. Tumor microenvironment has been shown to be a promising therapeutic target and diagnostic marker in extracranial malignancies. A better understanding of tumor microenvironment in the brain would therefore be expected to contribute to the development of improved therapies for brain tumors that are urgently required due to a poor availability of treatments for these malignancies. This review summarizes some of the known interactions between brain tumors and different stromal cells, and also discusses potential therapeutic approaches within this context.
Active Roles of Tumor Stroma in Breast Cancer Metastasis  [PDF]
Zahraa I. Khamis,Ziad J. Sahab,Qing-Xiang Amy Sang
International Journal of Breast Cancer , 2012, DOI: 10.1155/2012/574025
Abstract: Metastasis is the major cause of death for breast cancer patients. Tumors are heterogenous cellular entities composed of cancer cells and cells of the microenvironment in which they reside. A reciprocal dynamic interaction occurs between the tumor cells and their surrounding stroma under physiological and pathological conditions. This tumor-host communication interface mediates the escape of tumor cells at the primary site, survival of circulating cancer cells in the vasculature, and growth of metastatic cancer at secondary site. Each step of the metastatic process is accompanied by recruitment of stromal cells from the microenvironment and production of unique array of growth factors and chemokines. Stromal microenvironment may play active roles in breast cancer metastasis. Elucidating the types of cells recruited and signal pathways involved in the crosstalk between tumor cells and stromal cells will help identify novel strategies for cotargeting cancer cells and tumor stromal cells to suppress metastasis and improve patient outcome. 1. Introduction Breast cancer is the most common malignancy and the second major cause of mortality and morbidity in Western women [1]. The systemic outgrowth and spread of the cancer cells through a process known as metastasis is the main cause of deaths in these patients. Recently, disease-related mortality and metastasis have declined as a result of early diagnosis and application of adjuvant therapy. Mammographic screening, surgery, radiotherapy, chemotherapy, antibody therapy, and endocrine therapy facilitate the suppression of the metastatic dissemination of local tumor [2]. However, these treatments target the tumor cells and disregard the auxiliary cells present in the surrounding microenvironment that is also referred to as the stromal cells. These auxiliary cells, including myoepithelial cells, fibroblasts, myofibroblasts, endothelial cells, inflammatory cells, and bone-marrow-derived cells (BMDCs) such as macrophages, mast cells, neutrophils, and lymphocytes, are widely recognized to collaborate with cancerous cells and other host cells to create a tumor-permissive microenvironment capable of providing continuous support for tumor growth, progression, angiogenesis, invasion, and metastasis [3, 4]. Metastasis is the systemic dissemination of tumor cells at sites distinct from the primary lesion. It is a multistep process that involves detachment of cells from the primary tumor, followed by survival in the blood vessels or lymphatic system and finally development of secondary tumor. It is a poorly understood
Multiple Myeloma Macrophages: Pivotal Players in the Tumor Microenvironment  [PDF]
Simona Berardi,Roberto Ria,Antonia Reale,Annunziata De Luisi,Ivana Catacchio,Michele Moschetta,Angelo Vacca
Journal of Oncology , 2013, DOI: 10.1155/2013/183602
Abstract: Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM) microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management. 1. Tumor-Associated Macrophages In the past decades, the major focus of cancer research has been the malignant cell itself. In haematological malignancies, including multiple myeloma (MM), this has led to the identification of molecular alterations affecting growth control and apoptotic pathways [1]. Recent studies add yet another facet to the complex multistep model of tumorigenesis by demonstrating that tumor cells carrying genomic and epigenomic abnormalities also trigger changes in their microenvironment [2]. Indeed, accumulating evidence supports the hypothesis that the tumor microenvironment or “niche” ultimately determines the clinical behavior of the disease and has direct impact on overall prognosis [3]. MM is characterized by the accumulation of monoclonal plasma cells in the bone marrow (BM) where they grow and expand. This suggests the importance of the BM microenvironment in supporting MM cell growth and survival [4]. The roles of BM stromal cells in supporting MM plasma cells have been extensively studied. The interaction between plasma cells and stromal cells confers plasma cell homing, growth, survival, and resistance to chemotherapy [5]. Among stromal cells, the inflammatory cells play an indispensable role in disease progression [6]. Within the tumor stroma, the macrophage is the pivotal member of inflammatory cells. Tumor-associated macrophages (TAMs), which constitute a significant part of
Tumor Microenvironment-the Critical Element of Tumor Metastasis  [PDF]
Fang YANG, Yan YU
- , 2015, DOI: : 10.3779/j.issn.1009-3419.2015.01.08
Abstract: Metastasis is the main reason for the failure of cancer therapy and the death of patients. The molecular mechanism is complex, involving the change of multi-step, multi-stage and multi-gene. As the survival places of tumor cells, the tumor microenvironment plays a crucial role in tumor metastasis. Therefore, the study of the dynamic relationship between the tumor microenvironment and tumor metastasis, to clarify the molecular mechanisms in the metastasis process is the key point to inhibit the tumor metastasis.
Platinum-Sensitive Recurrence in Ovarian Cancer: The Role of Tumor Microenvironment  [PDF]
Jeremy Chien,Rui Kuang,Charles Landen,Viji Shridhar
Frontiers in Oncology , 2013, DOI: 10.3389/fonc.2013.00251
Abstract: Despite several advances in the understanding of ovarian cancer pathobiology, in terms of driver genetic alterations in high-grade serous cancer, histologic heterogeneity of epithelial ovarian cancer, cell-of-origin for ovarian cancer, the survival rate from ovarian cancer is disappointingly low when compared to that of breast or prostate cancer. One of the factors contributing to the poor survival rate from ovarian cancer is the development of chemotherapy resistance following several rounds of chemotherapy. Although unicellular drug resistance mechanisms contribute to chemotherapy resistance, tumor microenvironment and the extracellular matrix (ECM), in particular, is emerging as a significant determinant of a tumor’s response to chemotherapy. In this review, we discuss the potential role of the tumor microenvironment in ovarian cancer recurrence and resistance to chemotherapy. Finally, we propose an alternative view of platinum-sensitive recurrence to describe a potential role of the ECM in the process.
The role of the microenvironment in tumor immune surveillance  [cached]
Oluwadayo Oluwadara,Luca Giacomelli,Xenia Brant,Russell Christensen4
Bioinformation , 2011,
Abstract: The evidence appears compelling that the microenvironment, and associated biological cellular and molecular factors, may contribute to the progression of a variety of tumors. The effects of the microenvironment may directly influence the plasticity of T cell lineages, which was recently discussed (O’Shea & Paul, 2010 ). To review the putative role of the microenvironment in modulating the commitment of tumor immune surveillance, we use the model of oral premalignant lesions.
Interaction of tumor cells with the microenvironment
Hendrik Ungefroren, Susanne Sebens, Daniel Seidl, Hendrik Lehnert, Ralf Hass
Cell Communication and Signaling , 2011, DOI: 10.1186/1478-811x-9-18
Abstract: The complex process of metastasis formation can be divided into several stages: emigration from the primary tumor, invasion of the surrounding tissue and its extracellular matrix (ECM), intravasation into the circulation or the lymphatic system via transmigration through the endothelial lining and the basement membrane, and finally extravasation and metastasis formation at target sites. During each stage, tumor cells have to detach, migrate, invade, adapt and re-attach by involving matrix degrading enzymes and mechanical processes such as cell adhesion, changes of cell fate, cell movements and motility, and the generation of forces. Indeed, an understanding of the invasion process is only possible in the context of detailed insights into the cancer cell's interactions with the microenvironment. These interactions are determined by structural and biochemical properties of the ECM as well as by communication with surrounding non-neoplastic cells such as endothelial cells (ECs, during the process of transendothelial migration), cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSC), and a variety of different immune cells including lymphocytes and tumor-associated macrophages (TAMs). Since these multiple interactions with the tumor stroma determine not only cancer growth and metastasis but may also develop protective effects with respect to the tumor cells' drug sensitivity/resistance, the tumor stroma also has to be considered as a potential therapeutic target. Specifically, a deeper understanding of these interactions will elucidate the mechanisms of action of classical drugs that have been discovered by empirical approaches and, even more appealing, will facilitate the design and development of novel mechanistically-acting or even individually-designed drugs. This particularly applies for tumors exhibiting a pronounced stromal compartment such as invasive mammary adenocarcinoma (MaCa) and the highly malignant pancreatic ductal adenocarcinoma (PDAC), the
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