Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation.
TL;DR: It is reported that TGF-β1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis, and downregulation of isocitrate dehydrogenase 3α (IDH3α) is identified as a marker for this switch.
About: This article is published in Cell Reports.The article was published on 2015-03-03 and is currently open access. It has received 249 citations till now. The article focuses on the topics: Anaerobic glycolysis & Oxidative phosphorylation.
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TL;DR: Tumor microenvironment is a major contributor to tumor growth, metastasis and resistance to therapy, which consists of many cancer-associated fibroblasts (CAFs), which derive from different types of cells.
Abstract: Simple Summary Tumor microenvironment is a major contributor to tumor growth, metastasis and resistance to therapy. It consists of many cancer-associated fibroblasts (CAFs), which derive from different types of cells. CAFs detected in different tumor types are linked to poor prognosis, as in the case of colorectal cancer. Although their functions differ according to their subtype, their detection is not easy, and there are no established markers for such detection. They are possible targets for therapeutic treatment. Many trials are ongoing for their use as a prognostic factor and as a treatment target. More research remains to be carried out to establish their role in prognosis and treatment. Abstract The therapeutic approaches to cancer remain a considerable target for all scientists around the world. Although new cancer treatments are an everyday phenomenon, cancer still remains one of the leading mortality causes. Colorectal cancer (CRC) remains in this category, although patients with CRC may have better survival compared with other malignancies. Not only the tumor but also its environment, what we call the tumor microenvironment (TME), seem to contribute to cancer progression and resistance to therapy. TME consists of different molecules and cells. Cancer-associated fibroblasts are a major component. They arise from normal fibroblasts and other normal cells through various pathways. Their role seems to contribute to cancer promotion, participating in tumorigenesis, proliferation, growth, invasion, metastasis and resistance to treatment. Different markers, such as a-SMA, FAP, PDGFR-β, periostin, have been used for the detection of cancer-associated fibroblasts (CAFs). Their detection is important for two main reasons; research has shown that their existence is correlated with prognosis, and they are already under evaluation as a possible target for treatment. However, extensive research is warranted.
6 citations
01 Jan 2016
TL;DR: It is observed that FAP protease promotes pancreatic cancer development, as its deletion delays the progression of preneoplastic lesions and tumor formation in a genetically engineered mouse model of pancreatic ductal carcinoma.
Abstract: Primary carcinomas and metastases are complex organ-like structures composed of malignant parenchymal epithelial tissues and a desmoplastic stroma formed by accumulation of hematopoietic cells, mesenchymal stromal cells and extracellular matrix. The crosstalk between malignant epithelial cells and tumor stroma is becoming increasingly appreciated as a key determinant in tumor development, progression and metastasis, as well as inducing resistance to various cancer treatments including chemotherapy, radiotherapy and immunotherapy. Mechanistic understanding of how the tumor-stromal interaction contributes to tumor progression and therapeutic resistance will advance cancer therapies and improve clinical management, especially for patients with metastatic disease. Fibroblast activation protein (FAP) is a membrane surface protease found overexpressed in cancer-associated stromal cells. Overexpression of FAP is associated with tumor progression, metastasis and recurrence, and predicts a poorer prognosis in many types of human tumors. The central goal of my thesis project is to investigate whether FAP protease and/or FAP proteaseexpressing stromal cells play essential roles in tumor progression and metastasis. In collaboration with Drs. Steven Albelda and Carl June’s groups, we generated chimeric antigen receptor (CAR) T cells redirected against FAP+ stromal cells to study their impact on tumor progression. Conditional depletion of FAP+ stromal cells by FAP-CAR T cells restrains tumor progression without causing severe toxicity. Mechanistic investigations revealed that FAP+ stromal cells promote tumor growth via immune suppression and immuneindependent remodeling of the stromal microenvironment. Additionally, using FAP-deficient mice, I found that FAP protease promotes early malignant cell seeding and pulmonary metastatic outgrowth, possibly through regulating coagulation pathways and the inflammatory response, respectively. Finally, I observed that FAP protease promotes pancreatic cancer development, as its deletion delays the progression of preneoplastic lesions and tumor formation in a genetically engineered mouse model of pancreatic ductal carcinoma. FAP protease is also essential for inducing pancreatic cancer resistance to necrotic cell death and promoting metastasis and outgrowth in multiple target organs. Together, these findings demonstrate that molecular and cellular targeting of FAP represents a promising therapeutic approach for a variety of solid tumors. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Ellen Pure This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1862
6 citations
TL;DR: In this article, the effects of chemotherapeutic agents on normal cellular components of the host-derived tumor microenvironment focusing on CAFs were reviewed and synthesize findings from studies focusing on other cancer types and benign tissues.
Abstract: High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor-stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.
6 citations
TL;DR: The co-injection model of tumor cells with retrovirus-modified fibroblasts proved a valid method to identify tumor-modulating genes in TAFs, allowing for a deeper insight into the role of the stroma for tumor development.
Abstract: // Lijie Rong 1, 2, 3, * , Yangyang Bian 1, * , Shubai Liu 2, 3, * , Xiaoman Liu 2, 3 , Xiao Li 2, 3, ** , Haiyang Liu 2, 3, 4 , Jinxue Zhou 5 , Jirun Peng 6, 7, 8 , Henghui Zhang 9 , Hongsong Chen 9 and Zhihai Qin 1, 2, 3 1 Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China 2 Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo, Beijing, 100101, China 3 Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China 4 University of Chinese Academy of Sciences, Beijing, 100049, China 5 Henan Tumor Hospital, Zhengzhou, 450008, China 6 Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China 7 Capital Medical University Clinical Cancer Center, Beijing, 100038, China 8 Ninth Clinical Medical College of Peking University, Beijing, 100038, China 9 Peking University People's Hospital, Peking University Hepatology Institute, Beijing, 100044, China * These authors have contributed equally to this work ** Current Address: Beijing Institute For Drug Control, Beijing, 102206, China Correspondence to: Zhihai Qin, email: zhihai@ibp.ac.cn Keywords: Tumor-associated fibroblasts, retrovirus-insertional mutagenesis, tumor-promoting gene, co-injection model, Ttl Received: July 04, 2017 Accepted: September 21, 2017 Published: October 16, 2017 ABSTRACT Tumor-associated fibroblasts (TAFs) are often essential for solid tumor growth. However, few genetic or epigenetic alterations have been found in TAFs during the progression of solid tumors. Employing a tumor-stromal cell co-injection model, we adapted here retroviral-insertional mutagenesis to stromal cells to identify novel tumor-associated genes in TAFs. We successfully identified 20 gene candidates that might modulate tumor growth if altered in TAFs at genomic level. To validate our finding, the function of one of the candidate genes, tubulin tyrosine ligase ( Ttl ), was further studied in TAFs from fibrosarcoma, colon, breast and hepatocarcinoma. We demonstrated that down-regulated TTL expression in TAFs indeed promoted tumor growth in mice. Interestingly, decreased expression of TTL in tumor stromal cells also correlated with poor outcome in human colon carcinoma. Thus, the co-injection model of tumor cells with retrovirus-modified fibroblasts proved a valid method to identify tumor-modulating genes in TAFs, allowing for a deeper insight into the role of the stroma for tumor development.
6 citations
Cites background from "Metabolic reprogramming of cancer-a..."
...Zhang D, Wang Y, Shi Z, Liu J, Sun P, Hou X, Zhang J, Zhao S, Zhou BP, Mi J. Metabolic reprogramming of cancerassociated fibroblasts by IDH3α downregulation....
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...Using artificial tumor microenvironments, gene expression profiling of fibroblasts co-cultured with tumor cells [16], or growth factor induced TAFs [17], also revealed altered genes in TAFs that functionally associated with tumor growth, such as IDH3α[17]....
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TL;DR: In this article, the authors discuss the underlying characteristics of breast CAFs, mechanisms of metabolic reprogramming in breast CAF, and the nature of interactions between CAFs and cancer cells to studying the intricacies of reprogrammed metabolism targeted cancer therapy.
6 citations
References
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TL;DR: It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration.
Abstract: Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.
12,395 citations
TL;DR: Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases and integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases, but owing to several unanswered questions, caution is needed.
Abstract: Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases But owing to several unanswered questions, caution is needed
8,561 citations
"Metabolic reprogramming of cancer-a..." refers background in this paper
...The development and progression of tumors are controlled not only by tumor cells but also by their surrounding stromal cells (Carmeliet and Jain, 2000; Rønnov-Jessen et al., 1996; Tlsty, 2001)....
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TL;DR: Using a coimplantation tumor xenograft model, it is demonstrated that carcinoma-associated fibroblasts extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammaries derived from the same patients.
3,373 citations
"Metabolic reprogramming of cancer-a..." refers background in this paper
..., 1999), progression (Dimanche-Boitrel et al., 1994; Orimo et al., 2005), and metastasis (Grum-Schwensen et al....
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...Through specific communications with cancer cells, CAFs directly promote tumor initiation (Bhowmick et al., 2004; Olumi et al., 1999), progression (Dimanche-Boitrel et al., 1994; Orimo et al., 2005), and metastasis (Grum-Schwensen et al., 2005; Olaso et al., 1997)....
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TL;DR: The basement membrane (BM) as mentioned in this paper is a specialized form of extracellular matrix (ECM) which mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment.
Abstract: In recent years, the basement membrane (BM)--a specialized form of extracellular matrix (ECM)--has been recognized as an important regulator of cell behaviour, rather than just a structural feature of tissues. The BM mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment. The BM is also an important structural and functional component of blood vessels, constituting an extracellular microenvironment sensor for endothelial cells and pericytes. Vascular BM components have recently been found to be involved in the regulation of tumour angiogenesis, making them attractive candidate targets for potential cancer therapies.
1,560 citations
TL;DR: In this paper, the authors demonstrate that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in vitro coculture system.
Abstract: The present study demonstrates that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in an in vitro coculture system. Human prostatic carcinoma-associated fibroblasts grown with initiated human prostatic epithelial cells dramatically stimulated growth and altered histology of the epithelial population. This effect was not detected when normal prostatic fibroblasts were grown with the initiated epithelial cells under the same experimental conditions. In contrast, carcinoma-associated fibroblasts did not affect growth of normal human prostatic epithelial cells under identical conditions. From these data, we conclude that in this human prostate cancer model, carcinoma-associated fibroblasts stimulate progression of tumorigenesis. Thus, carcinoma-associated fibroblasts can direct tumor progression of an initiated prostate epithelial cell.
1,486 citations