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Journal ArticleDOI

Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth.

11 Dec 2015-Cancers (Multidisciplinary Digital Publishing Institute (MDPI))-Vol. 7, Iss: 4, pp 2443-2458
TL;DR: It is shown that CAFs are an important IL-6 source and that anti-IL-6 receptor antibody suppressed angiogenesis and inhibited tumor-stroma interactions, and CAFs contribute to drug-resistance acquisition in cancer cells.
Abstract: Cancer tissues are composed of cancer cells and the surrounding stromal cells (e.g., fibroblasts, vascular endothelial cells, and immune cells), in addition to the extracellular matrix. Most studies investigating carcinogenesis and the progression, invasion, metastasis, and angiogenesis of cancer have focused on alterations in cancer cells, including genetic and epigenetic changes. Recently, interactions between cancer cells and the stroma have attracted considerable attention, and increasing evidence has accumulated on this. Several researchers have gradually clarified the origins, features, and roles of cancer-associated fibroblasts (CAFs), a major component of the cancer stroma. CAFs function in a similar manner to myofibroblasts during wound healing. We previously reported the relationship between CAFs and angiogenesis. Interleukin-6 (IL-6), a multifunctional cytokine, plays a central role in regulating inflammatory and immune responses, and important roles in the progression, including proliferation, migration, and angiogenesis, of several cancers. We showed that CAFs are an important IL-6 source and that anti-IL-6 receptor antibody suppressed angiogenesis and inhibited tumor-stroma interactions. Furthermore, CAFs contribute to drug-resistance acquisition in cancer cells. The interaction between cancer cells and the stroma could be a potential target for anti-cancer therapy.

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Citations
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Journal ArticleDOI
TL;DR: An overview of the advances in understanding the complex cancer cell–tumour stroma interactions is provided and how this knowledge can result in more effective therapeutic strategies, which might ultimately improve patient outcomes are discussed.
Abstract: Cancers are not composed merely of cancer cells alone; instead, they are complex ‘ecosystems’ comprising many different cell types and noncellular factors. The tumour stroma is a critical component of the tumour microenvironment, where it has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote the resistance of cancer cells to such therapies, eventually resulting in fatal disease. Therefore, novel treatment strategies should combine anticancer and antistromal agents. Herein, we provide an overview of the advances in understanding the complex cancer cell–tumour stroma interactions and discuss how this knowledge can result in more effective therapeutic strategies, which might ultimately improve patient outcomes.

657 citations

Journal ArticleDOI
TL;DR: This review article summarized the recent progress in various nanoformulations for cancer therapy, with a special emphasis on tumour microenvironment stimuli-responsive ones, which it believes offer a good chance for the practical translation of nanoparticle formulas into clinic.
Abstract: Nanovehicles can efficiently carry and deliver anticancer agents to tumour sites Compared with normal tissue, the tumour microenvironment has some unique properties, such as vascular abnormalities, hypoxia and acidic pH There are many types of cells, including tumour cells, macrophages, immune and fibroblast cells, fed by defective blood vessels in the solid tumour Exploiting the tumour microenvironment can benefit the design of nanoparticles for enhanced therapeutic effectiveness In this review article, we summarized the recent progress in various nanoformulations for cancer therapy, with a special emphasis on tumour microenvironment stimuli-responsive ones Numerous tumour microenvironment modulation strategies with promising cancer therapeutic efficacy have also been highlighted Future challenges and opportunities of design consideration are also discussed in detail We believe that these tumour microenvironment modulation strategies offer a good chance for the practical translation of nanoparticle formulas into clinic

632 citations

Journal ArticleDOI
TL;DR: The key roles of the IL-6 cytokine family in regulating innate and adaptive immunity, as well as other physiological responses are considered, which highlight the potential of targeting IL- 6 family members to treat inflammatory diseases and cancer.
Abstract: The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease.

563 citations

Book ChapterDOI
TL;DR: Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines and are of potential interest as noninvasive biomarkers of cancer.
Abstract: Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation.

511 citations

Journal ArticleDOI
TL;DR: Applying multimodal intersection analysis to primary pancreatic tumors, it is found that subpopulations of ductal cells, macrophages, dendritic cells and cancer cells have spatially restricted enrichments, as well as distinct coenrichments with other cell types.
Abstract: Single-cell RNA sequencing (scRNA-seq) enables the systematic identification of cell populations in a tissue, but characterizing their spatial organization remains challenging. We combine a microarray-based spatial transcriptomics method that reveals spatial patterns of gene expression using an array of spots, each capturing the transcriptomes of multiple adjacent cells, with scRNA-Seq generated from the same sample. To annotate the precise cellular composition of distinct tissue regions, we introduce a method for multimodal intersection analysis. Applying multimodal intersection analysis to primary pancreatic tumors, we find that subpopulations of ductal cells, macrophages, dendritic cells and cancer cells have spatially restricted enrichments, as well as distinct coenrichments with other cell types. Furthermore, we identify colocalization of inflammatory fibroblasts and cancer cells expressing a stress-response gene module. Our approach for mapping the architecture of scRNA-seq-defined subpopulations can be applied to reveal the interactions inherent to complex tissues.

449 citations

References
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Journal ArticleDOI
Otto Warburg1
24 Feb 1956-Science

10,654 citations

01 Jan 1956

8,572 citations


"Cancer-Associated Fibroblasts: Thei..." refers background in this paper

  • ...This phenomenon is known as “Warburg effect” [84]....

    [...]

Journal ArticleDOI
TL;DR: The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult.
Abstract: The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult1 Neovascularization (angiogenesis) is also implicated in the pathogenesis of a number of disorders These include: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis1,2 A strong correlation has been noted between density of microvessels in primary breast cancers and their nodal metastases and patient survival3 Similarly, a correlation has been reported between vascularity and invasive behavior in several other tumors4–6

4,603 citations


"Cancer-Associated Fibroblasts: Thei..." refers background in this paper

  • ...In 1989, Ferrara discovered vascular endothelial growth factor (VEGF), which is a key angiogenic factor [68]....

    [...]

Journal Article

4,173 citations


"Cancer-Associated Fibroblasts: Thei..." refers background in this paper

  • ...already proposed the importance of the tumor microenvironment with the theory of “seed & soil” [1]....

    [...]

Journal ArticleDOI
TL;DR: Tumors of epithelioma are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.
Abstract: SOLID tumors are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.1 , 2 In tumors of epitheli...

4,132 citations


"Cancer-Associated Fibroblasts: Thei..." refers background in this paper

  • ...proposed the theory that a “tumor is a wound that never heals” [2]....

    [...]