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Tumor Microenvironment And Therapeutic Resistance In Gynecologic Malignancies
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Book Synopsis Tumor Microenvironment and Therapeutic Resistance in Gynecologic Malignancies by : Xia Bai Rong
Download or read book Tumor Microenvironment and Therapeutic Resistance in Gynecologic Malignancies written by Xia Bai Rong and published by Frontiers Media SA. This book was released on 2023-02-02 with total page 132 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Molecular Diagnosis and Targeting for Gynecologic Malignancy by : Seiji Isonishi
Download or read book Molecular Diagnosis and Targeting for Gynecologic Malignancy written by Seiji Isonishi and published by Springer Nature. This book was released on 2021-03-05 with total page 171 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book summarizes the important developments in the field of cancer research, specifically uterine cervical/endometrial cancer and ovarian cancer. It highlights the recent advances in gynecologic cancer, such as next generation models of genetically engineered animal models or cancer cell lines, focusing on their significance for advancing our understanding of gynecologic cancer biology, prevention and treatment, and drug response and resistance. Cancer research in the area of gynecologic tumors has undergone an enormous transformation over the past decade, with a greater understanding of tumor biology, elucidation of novel targets for therapeutic intervention, and better recognition of genetic predisposition syndromes. At the same time, the recent advances in basic cancer research have provided key insights into all aspects of gynecologic cancer biology, including developmental pathways and the impact of lineage plasticity, understanding metastatic progression, uncovering the roles of the tumor microenvironment , exploring tumor evolution, and discovering new therapeutic approaches and mechanisms of drug sensitivity and adaptive response. Molecular Diagnosis and Targeting for Gynecologic Malignancy appeals to investigators, clinicians, residents and postdocs who are curious about new research on gynecologic malignancies. It not only presents basic and translational research, but also explores the generalizability of the evidence covering the interface between basic and clinical science. Furthermore, a number of the topics offer the basis for new ideas that have the potential to advance into the gynecologic malignancies. This book provides readers with state-of-the-art information that will help improve the lives of patients with these challenging diseases.
Book Synopsis Overcoming Drug Resistance in Gynecologic Cancers by :
Download or read book Overcoming Drug Resistance in Gynecologic Cancers written by and published by Elsevier. This book was released on 2021-08-17 with total page 388 pages. Available in PDF, EPUB and Kindle. Book excerpt: Overcoming Drug Resistance in Gynecologic Cancers provides up-to-date information related to important gynecologic cancers and focuses on mechanisms of drug resistance, genetics, signaling, immunology, health disparities, nanotechnology, economic considerations and financial impacts. The book covers not only drug resistance but also important means to reverse resistance both in the laboratory and clinic. The book discusses topics such as lifestyle, nutrition and risk of gynecologic cancers, the financial impact of drug resistance, chemosensitizing agents and targeted therapies in cervical, endometrial and ovarian cancer, immunotherapy to overcome drug resistance, and genetic polymorphisms in gynecologic cancers. Additionally, it discusses ethnic and racial health disparity perspectives and future developments in chemosensitizing activities to reverse drug resistance in gynecologic cancers. It is a valuable resource for cancer researchers, oncologists, clinicians and other biomedical field members who are interested in new approaches to improve chemotherapy outcome in patients with gynecologic cancers. Provides a comprehensive resource with all the details needed for readers to understand and follow information Encompasses schematics, diagrams and flow charts in all chapters to help readers easily follow critical information Presents tables and figures especially developed to summarize the information with appropriate statistical rigor and to show details of clinical specimens such as pathological, radiological characteristics, and/or laboratory biomarkers
Book Synopsis Overcoming Drug Resistance in Gynecologic Cancers by :
Download or read book Overcoming Drug Resistance in Gynecologic Cancers written by and published by Academic Press. This book was released on 2021-08-11 with total page 390 pages. Available in PDF, EPUB and Kindle. Book excerpt: Overcoming Drug Resistance in Gynecologic Cancers provides up-to-date information related to important gynecologic cancers and focuses on mechanisms of drug resistance, genetics, signaling, immunology, health disparities, nanotechnology, economic considerations and financial impacts. The book covers not only drug resistance but also important means to reverse resistance both in the laboratory and clinic. The book discusses topics such as lifestyle, nutrition and risk of gynecologic cancers, the financial impact of drug resistance, chemosensitizing agents and targeted therapies in cervical, endometrial and ovarian cancer, immunotherapy to overcome drug resistance, and genetic polymorphisms in gynecologic cancers. Additionally, it discusses ethnic and racial health disparity perspectives and future developments in chemosensitizing activities to reverse drug resistance in gynecologic cancers. It is a valuable resource for cancer researchers, oncologists, clinicians and other biomedical field members who are interested in new approaches to improve chemotherapy outcome in patients with gynecologic cancers. Provides a comprehensive resource with all the details needed for readers to understand and follow information Encompasses schematics, diagrams and flow charts in all chapters to help readers easily follow critical information Presents tables and figures especially developed to summarize the information with appropriate statistical rigor and to show details of clinical specimens such as pathological, radiological characteristics, and/or laboratory biomarkers
Book Synopsis Peritoneal Tumor Microenvironment of Cancers on Cancer Hallmarks by : Yong Sang Song
Download or read book Peritoneal Tumor Microenvironment of Cancers on Cancer Hallmarks written by Yong Sang Song and published by Elsevier. This book was released on 2024-06-28 with total page 380 pages. Available in PDF, EPUB and Kindle. Book excerpt: Peritoneal Tumor Microenvironment of Cancers on Cancer Hallmarks: Perspectives of Translational Medicine provides readers with cutting-edge knowledge on tumor microenvironment. By exploring multiple aspects on tumor microenvironment, it gives an integrative insight on cancer diseases ranging from diagnosis to prediction of prognosis and individualized treatment.The book discusses topics such as clinical significance of tumor microenvironment, tumorigenesis and cancer progression, histopathological features of cancer in peritoneum, immune cells in tumor, exosomal cell-to-cell interactions, and therapeutic approaches to target tumor microenvironment. Additionally, it discusses tumor evolution during chemotherapy and metastasis, and future perspectives on identification and validation of biomarkers using liquid biopsy. This book is a valuable resource for cancer researchers, oncologists, medical doctors, and several members of biomedical field who want to understand the complex microenvironment of peritoneal tumors. Discusses how to apply tumor microenvironment knowledge to diagnosis, prediction of prognosis, and individualized treatment of cancer Provides readers with up-to-date knowledge on translational medicine, focusing on bench-to-bedside approach for cancer treatment and diagnosis Presents collaborative research works from the perspectives of medical doctors, cancer researchers, basic biological scientists, and bioinformaticians to provide integrative insights on tumor microenvironment
Book Synopsis The Tumor Microenvironment of High Grade Serous Ovarian Cancer by : M. Sharon Stack
Download or read book The Tumor Microenvironment of High Grade Serous Ovarian Cancer written by M. Sharon Stack and published by MDPI. This book was released on 2019-02-06 with total page 435 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book is a printed edition of the Special Issue "The Tumor Microenvironment of High Grade Serous Ovarian Cancer" that was published in Cancers
Book Synopsis Tumor microenvironment, immunotherapy, and drug resistance in breast and gastrointestinal cancer by : Shaoquan Zheng
Download or read book Tumor microenvironment, immunotherapy, and drug resistance in breast and gastrointestinal cancer written by Shaoquan Zheng and published by Frontiers Media SA. This book was released on 2023-09-29 with total page 156 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis The Tumor Microenvironment: Recent Advances and Novel Therapeutic Approaches by : Sandra Orsulic
Download or read book The Tumor Microenvironment: Recent Advances and Novel Therapeutic Approaches written by Sandra Orsulic and published by Frontiers Media SA. This book was released on 2021-12-03 with total page 157 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Diagnosis and Treatment of Rare Gynecologic Cancers by : Michael Frumovitz
Download or read book Diagnosis and Treatment of Rare Gynecologic Cancers written by Michael Frumovitz and published by Elsevier Health Sciences. This book was released on 2022-05-10 with total page 387 pages. Available in PDF, EPUB and Kindle. Book excerpt: Offering a one-stop guide to recognition and therapeutic decision making, Diagnosis and Treatment of Rare Gynecologic Cancers fills a gap in the medical literature on uncommon ovarian, uterine, cervical, and vulvovaginal cancers and trophoblastic diseases. This authoritative text, edited by Drs. Michael Frumovitz, Mario Leitao, and Preetha Ramalingam, has been authored by internationally recognized experts from top institutions such as MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center. Each chapter covers different cancer subtypes and has been reviewed by an oncologist and a pathologist. Provides up-to-date clinical guidance on assessment and therapeutic options for patients with rare gynecologic malignancies. Presents information in a templated, easy-to-read format. Each chapter includes an introductory clinical case followed by epidemiology of disease, pathologic assessment, basic science/molecular/translational research, work-up of newly diagnosed disease, staging, treatment of newly diagnosed disease, treatment of recurrent disease, potential therapeutic targets, and a case resolution. Includes diagnostic and treatment algorithms for each form of cancer. Contains numerous anatomical figures, radiographs, photographs, and tables for quick visual reference.
Book Synopsis Overcoming Ovarian Cancer Chemoresistance by : Goli Samimi
Download or read book Overcoming Ovarian Cancer Chemoresistance written by Goli Samimi and published by Academic Press. This book was released on 2020-11-06 with total page 190 pages. Available in PDF, EPUB and Kindle. Book excerpt: Overcoming Ovarian Cancer Chemoresistance presents non-overlapping review chapters that discuss the state of the field in overcoming chemoresistance of ovarian cancer and treatment options before and following recurrence, considering the genetic makeup of the ovarian cancer patient and her tumor. With the uptake of both germline and somatic gene testing, clinicians can obtain a more comprehensive understanding of ovarian tumors and this book provides information to link the genetic makeup of a tumor (or patient) with the best available treatment. The book discusses topics such as strategies to fight chemo-resistance in ovarian cancer, circulating DNA as a monitor of response, BRCA mutations, ovarian cancer stem cells, immunotherapy and vaccines. Additionally, it brings a list of promising agents at clinical and pre-clinical stage that will impact the treatment in the near future. This book is a valuable source for cancer researchers, oncologists and several members of biomedical field who need to understand how to battle chemoresistance in ovarian cancer. Provides a comprehensive view of both biological and genetic determinants of resistance, as well as technical approaches to monitor response Discusses genetic reversions as a unique alteration and a new field of study Includes a chapter on upcoming and promising agents that are in the pre-clinical and early clinical space, to set the stage for future directions in the field
Book Synopsis Metronomic Chemotherapy by : Guido Bocci
Download or read book Metronomic Chemotherapy written by Guido Bocci and published by Springer. This book was released on 2014-09-04 with total page 302 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book analyzes all aspects of metronomic chemotherapy, a new approach involving low-dose, long-term, and frequently administered therapy that has preclinical and clinical activity in various tumors. After an opening section on the pharmacological bases of metronomic chemotherapy, including its antiangiogenic effects and impact on immunity, preclinical studies on various classes of drug are discussed. Clinical applications of metronomic chemotherapy in a wide variety of tumors are then addressed in detail, with description of the results of all published studies. The clinical pharmacology of metronomic chemotherapy is also considered in depth, encompassing pharmacokinetics, pharmacogenetics, pharmacoeconomics, and adverse drug reactions. The book closes by describing the role of this therapy in the veterinarian clinic.
Book Synopsis Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic by : Peggy L. Carver
Download or read book Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic written by Peggy L. Carver and published by Walter de Gruyter GmbH & Co KG. This book was released on 2019-01-14 with total page 640 pages. Available in PDF, EPUB and Kindle. Book excerpt: Volume 19, entitled Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic of the series Metal Ions in Life Sciences centers on the role of metal ions in clinical medicine. Metal ions are tightly regulated in human health: while essential to life, they can be toxic as well. Following an introductory chapter briefly discussing several important metal-related drugs and diseases and a chapter about drug development, the focus is fi rst on iron: its essentiality for pathogens and humans as well as its toxicity. Chelation therapy is addressed in the context of thalassemia, its relationship to neurodegenerative diseases and also the risks connected with iron administration are pointed out. A subject of intense debate is the essentiality of chromium and vanadium. For example, chromium(III) compounds are taken as a nutritional supplement by athletes and bodybuilders; in contrast, chromate, Cr(VI), is toxic and a carcinogen for humans. The benefi cial and toxic effects of manganese, cobalt, and copper on humans are discussed. The need for antiparasitic agents is emphasized as well as the clinical aspects of metal-containing antidotes for cyanide poisoning. In addition to the essential and possibly essential ones, also other metal ions play important roles in human health, causing harm (like the metalloid arsenic, lead or cadmium) or being used in diagnosis or treatment of human diseases, like gadolinium, gallium, lithium, gold, silver or platinum. The impact of this vibrant research area on metals in the clinic is provided in 14 stimulating chapters, written by internationally recognized experts from the Americas, Europe and China, and is manifested by approximately 2000 references, and about 90 illustrations and tables. Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic is an essential resource for scientists working in the wide range from pharmacology, enzymology, material sciences, analytical, organic, and inorganic biochemistry all the way through to medicine ... not forgetting that it also provides excellent information for teaching.
Book Synopsis Holland-Frei Cancer Medicine by : Robert C. Bast, Jr.
Download or read book Holland-Frei Cancer Medicine written by Robert C. Bast, Jr. and published by John Wiley & Sons. This book was released on 2017-03-10 with total page 2008 pages. Available in PDF, EPUB and Kindle. Book excerpt: Holland-Frei Cancer Medicine, Ninth Edition, offers a balanced view of the most current knowledge of cancer science and clinical oncology practice. This all-new edition is the consummate reference source for medical oncologists, radiation oncologists, internists, surgical oncologists, and others who treat cancer patients. A translational perspective throughout, integrating cancer biology with cancer management providing an in depth understanding of the disease An emphasis on multidisciplinary, research-driven patient care to improve outcomes and optimal use of all appropriate therapies Cutting-edge coverage of personalized cancer care, including molecular diagnostics and therapeutics Concise, readable, clinically relevant text with algorithms, guidelines and insight into the use of both conventional and novel drugs Includes free access to the Wiley Digital Edition providing search across the book, the full reference list with web links, illustrations and photographs, and post-publication updates
Book Synopsis Immune Checkpoint Inhibitors in Cancer by : Fumito Ito
Download or read book Immune Checkpoint Inhibitors in Cancer written by Fumito Ito and published by Elsevier Health Sciences. This book was released on 2018-09-03 with total page 400 pages. Available in PDF, EPUB and Kindle. Book excerpt: Get a quick, expert overview of the latest clinical information and guidelines for cancer checkpoint inhibitors and their implications for specific types of cancers. This practical title by Drs. Fumito Ito and Marc Ernstoff synthesizes the most up-to-date research and clinical guidance available on immune checkpoint inhibitors and presents this information in a compact, easy-to-digest resource. It’s an ideal concise reference for trainee and practicing medical oncologists, as well as those in research. Discusses the current understanding of how to best harness the immune system against different types of cancer at various stages. Helps you translate current research and literature into practical information for daily practice. Presents information logically organized by disease site. Covers tumor immunology and biology; toxicities associated with immune checkpoint inhibitors; and future outlooks. Consolidates today’s available information on this timely topic into one convenient resource.
Book Synopsis A Theranostic and Precision Medicine Approach for Female-Specific Cancers by : Rama Rao Malla
Download or read book A Theranostic and Precision Medicine Approach for Female-Specific Cancers written by Rama Rao Malla and published by Academic Press. This book was released on 2020-11-06 with total page 320 pages. Available in PDF, EPUB and Kindle. Book excerpt: A Theranostic and Precision Medicine Approach for Female-Specific Cancers provides information regarding ongoing research and clinical data surrounding female specific cancers (breast, cervical, ovarian and endometrial cancers). The book encompasses detailed descriptions about diagnostics and therapeutic options for easy understanding, focusing on the subject matter with a broader range of treatment options. In addition, it explores new theranostics, i.e., diagnostic, therapeutic and precision medicine strategies currently being developed for FSCs. This book is a valuable resource for cancer researchers, clinicians, graduate students and other members of biomedical field who need to understand the most recent and promising approaches to manage FSCs. Explores new diagnostic biomarkers surrounding the early detection and prognosis of FSCs Examines new genetic and molecularly targeted approaches for the treatment of these aggressive diseases Discusses new theranostic approaches that combine diagnosis and treatment through the use of nanotechnology in FSCs Addresses how these various advances can be integrated into a precision and personalized medicine approach that can eventually enhance patient care
Book Synopsis Targeting Metabolic Vulnerabilities in Epithelial Ovarian Cancer Via Folate Transporters by : Adrianne Cecelia Wallace-Povirk
Download or read book Targeting Metabolic Vulnerabilities in Epithelial Ovarian Cancer Via Folate Transporters written by Adrianne Cecelia Wallace-Povirk and published by . This book was released on 2021 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Novel therapies are urgently needed for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy. In addition, therapies which target a unique vulnerability in the tumor microenvironment (TME) of EOC have largely been unrealized. It is known the major infiltrating immune population in EOC represents tumor-activated macrophages, yet it remains an enigma how the tumor has 0́−educated0́+ the niche to allow for tumor tolerance. To elucidate mechanisms for targeting EOC, we must discover metabolic vulnerabilities and establish mechanisms of selective delivery of therapeutic agents to tumors as well as immune cells, and investigate how the tumor has altered the metabolism of infiltrating macrophages, thus shaping the permissive environment for EOC. One strategy to achieve tumor cell and microenvironment selective drug delivery to EOC is by uptake via folate receptor (FR) and PCFT proteins, with internal targeting at mitochondrial and cytosolic one-carbon (C1) metabolism, pathways elevated in EOC patient tumors. FRÎł is highly expressed on up to 90% of EOC tumor cells, whereas FRÎø is expressed on activated 0́−M20́+ macrophages. PCFT is constitutively expressed in EOC. Thus, great potential exists to target both tumor and the TME with agents delivered via selective transport by FRs and/or PCFT. In this dissertation work, we discovered 6-substituted thieno[2,3-d]pyrimidine compounds, typified by AGF102, AGF103 and AGF131 with 3-4 bridge carbons and side-chain thiophene or furan rings for dual targeting C1 metabolism in FR expressing cancers. From patterns of growth inhibition toward Chinese hamster ovary cells expressing FRÎł or FRÎø, the proton-coupled folate transporter or reduced folate carrier, specificity for uptake by FRs was confirmed. Anti-proliferative activities were demonstrated toward FRÎł-expressing KB tumor cells and NCI-IGROV1 ovarian cancer cells. Inhibition of de novo purine biosynthesis at both 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase (GARFTase) was confirmed by metabolite rescue, metabolomics and enzyme assays. X-ray crystallographic structures were obtained with compounds AGF102, AGF103 and AGF131 and human GARFTase. Our studies identify first-in-class C1 inhibitors with selective uptake by FRs and dual inhibition of enzyme targets in de novo purine biosynthesis, resulting in anti-tumor activity. This series affords an exciting new platform for selective multi-targeted anti-tumor agents. In Aim 2, we discovered novel 5-substituted pyrrolo[3,2-d]pyrimidine analogs (AGF347, AGF359, and AGF362) as targeted agents for EOC. In vitro inhibition in the nanomolar range was seen with the FRÎł- and PCFT-expressing cisplatin-sensitive EOC cell line IGROV1 and cisplatin-resistant SKOV3 cells. Uptake by PCFT was demonstrated in IGROV1 and SKOV3 cells. shRNA knockdown of FRÎł (~95%) in IGROV1 cells resulted in a significantly decreased intracellular accumulation of [3H]AGF347, highlighting an important role for FRÎł in drug uptake. [3H]AGF347 treatment of IGROV1 EOC resulted in substantial drug accumulation in cytosol and mitochondria. Inhibition of C1 metabolism in mitochondria at serine hydroxymethyltransferase 2 (SHMT2), and de novo purine biosynthesis in the cytosol were implicated by metabolite 0́−rescue0́+ studies. Targeted metabolomics, using L-[2,3,3-2H]serine as a tracer in wild-type or SHMT2 knockdown SKOV3 cells, verified inhibition of mitochondrial C1-metabolism (at SHMT2) and de novo purine biosynthesis (at glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase). In vitro assays with purified recombinant proteins confirmed these intracellular enzyme targets. Secondary effects of SHMT2 inhibition were observed with all agents including depletion of reduced glutathione and mitochondrial NADH. Depletion of glutathione was accompanied by synergistic in vitro efficacy with AGF347 and cisplatin in SKOV3 cells. In vivo results against SKOV3 EOC xenografts with AGF347 and cisplatin in SCID mice confirmed cisplatin resistance, while AGF347 displayed potent anti-tumor efficacy. We extended our studies to investigate the impact of a cytosolic C1 inhibitor has upon the microenvironment in EOC, using a high-grade serous (HGS) syngeneic tumor model (BR-Luc). Previous studies revealed an important role for our previously characterized GARFTase inhibitor and FR and PCFT transport substrate, AGF94. Potent in vitro cytotoxicity was observed against the BR-Luc syngeneic model of HGS ovarian cancer. In vitro activity was extended to in vivo activity in both early and late stage trials of BR-Luc with AGF94. In late stage disease, our data revealed a direct impact upon M2-like FRÎø-expressing macrophages in syngeneic mice bearing HGS ovarian tumors and an increase in CD+ T cells, whereas CD4+ and CD8+ T cells were unaffected by AGF94 treatment. Collectively, our studies describe the development of novel mitochondria and cytosolic C1-metabolic inhibitors that are selectively delivered via FRs and PCFT, resulting in in vitro and in vivo activity against EOC. Our studies additionally lay an important framework to elucidate the complex TME of EOC, highlighting unique drug delivery mechanisms and metabolic vulnerabilities that EOC tumors employ, thus contributing to an immunosuppressive TME.
Book Synopsis Cancer Associated Fibroblasts Provide a Cancer Stem Cell Niche that Leads to Disease Relapse in Ovarian Cancer by : Yiming Fang (Biochemist)
Download or read book Cancer Associated Fibroblasts Provide a Cancer Stem Cell Niche that Leads to Disease Relapse in Ovarian Cancer written by Yiming Fang (Biochemist) and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Epithelial ovarian cancer is the most lethal gynecologic malignancy with a 5-year survival rate of only 48%. While most ovarian cancer patients respond to chemotherapy initially, frequent relapse (~80%) and development of chemoresistance result in poor patient outcomes. Cancer stem cells (CSCs) consist of a small subpopulation in the tumor that are capable of surviving from chemotherapy and causing tumor relapse. Using patient specimens and in vitro models, we determined that CSCs are enriched by cancer associated fibroblasts (CAFs) after chemotherapy. Cancer associated fibroblasts (CAFs) are a major constituent of the ovarian cancer tumor microenvironment and are highly enriched in the residual tumors following chemotherapy. Therefore, we studied the mechanism by which CAFs promote ovarian cancer chemoresistance and disease relapse. CAFs isolated from ovarian cancer patient tumors were used in heterotypic 2D or 3D coculture systems with high-grade serous ovarian cancer cell lines or with patient-derived ovarian cancer cells to study their effect on CSCs and chemoresistance. Matched pre-and post-chemotherapy patient tumors were used to confirm our findings. CAFs significantly increased adjacent cancer cell resistance to carboplatin by enriching CSCs. Pre-coculture with CAFs increased in vivo tumor initiation capacity of the ovarian cancer cells by 10-fold in limiting dilution assay analysis (ELDA) in mice. The CSC-CAF crosstalk responsible for CSC induction was found to be mediated by Wnt5a signaling. CRISPR knockdown of Wnt5a in CAFs or treatment with a specific Wnt5a inhibitor abrogated the induction of CSCs by CAFs. Only cancer cells with ROR2, a Wnt coreceptor, respond to Wnt5a signaling triggered by CAFs and developed into CSCs. Responders were found to signal through a non-canonical Wnt pathway involving the coreceptor ROR2, protein kinase C (PKC), and cAMP Responsive Element Binding Protein 1 (CREB1). Inhibition of each of them prevented CSC induction and functional rescue experiments were performed to confirm the sequence of the Wnt5a-ROR2-PKC-CREB1 axis. Treatment of mouse xenografts, established by co-injection of CAFs and ovarian cancer cells, with the Wnt5a inhibitor sensitized them to carboplatin, and eliminated the CSCs in the residual tumors. Our results indicate that CAF-derived Wnt5a is instrumental in ovarian cancer CSC growth and maintenance. Targeting Wnt5a in tumor effectively prevents tumor relapse after cytotoxic chemotherapy by destroying suitable CSC-enriching microenvironment. In the long term, our studies will broaden the understanding of the mechanism of CSC maintenance by the tumor microenvironment and contribute towards the development of novel therapeutic approaches to prevent ovarian cancer chemoresistance and relapse.
