Special Issue "Cancer-Associated Fibroblasts"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2015)

Special Issue Editor

Guest Editor
Dr. Huey-Jen Lin

Department of Medical Laboratory Sciences, College of Health Sciences, University of Delaware, Newark, DE 19716, USA
Website | E-Mail
Phone: +1-302-831-7576
Fax: +1-302-831-4180
Interests: DNA methylation; cancer invasion and metastasis in breast and pancreatic cancers; carcinoma-associated fibroblasts; epithelial-mesenchymal transition; AKT signaling pathway

Special Issue Information

Dear Colleagues,

During cancer progression, tumor cells secrete signaling molecules that influence the surrounding non-malignant cells that are collectively known as stroma or tumor microenvironment. Tumor stromal cells further favor tumor cell growth, survival, migration, invasion, micro-metastasis and colonization, as well as initiation of blood brain barrier transmigration. The malignant properties of growth, invasiveness, metastasis, and susceptibility to chemotherapeutic drugs are determined not only by cancer cells themselves, but also by the stromal microenvironment. Carcinoma-associated fibroblasts (CAFs) are the most active secretory and abundant population among the non-cancerous stromal cells, and CAFs are often associated with poor clinical prognosis. CAFs actively participate in tumor growth and metastasis by production of growth factors, metaloproteases, cytokines, chemokines, microRNA and the release of pro-inflammatory and pro-angiogenic factors. The roles that CAFs play during the initiation and progression of carcinogenesis are thought to be of critical importance, both for the enhanced understanding of fundamental cancer biology as well as for improving molecular diagnostics and therapeutics. Stromal fibroblasts have become one of the important predictors of disease-related mortality or efficacy of drug treatment. This Special Issue focuses on novel advances in understanding how CAFs provide cancer cells with a supportive microenvironment, as well as on the development of novel therapeutic regimens by abrogating the vicious cycle of tumor-stromal interactions.

Dr. Huey-Jen Lin
Guest Editor

Manuscript Submission Information

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Keywords

  • cancer-associated fibroblasts
  • cytokines
  • immunmodulation
  • epigenetics
  • signal transduction pathways
  • susceptibility to anti-cancer drugs
  • tumor microenvironment
  • tumor invasion and metastasis

Published Papers (8 papers)

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Research

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Open AccessFeature PaperArticle TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts
Cancers 2016, 8(11), 100; https://doi.org/10.3390/cancers8110100
Received: 30 August 2016 / Revised: 4 October 2016 / Accepted: 20 October 2016 / Published: 4 November 2016
Cited by 2 | PDF Full-text (3614 KB) | HTML Full-text | XML Full-text
Abstract
The TGF-β pathway plays a major role in tumor progression through regulation of epithelial and stromal cell signaling. Dysfunction of the pathway can lead to carcinoma progression and metastasis. To gain insight into the stromal role of the TGF-β pathway in breast cancer,
[...] Read more.
The TGF-β pathway plays a major role in tumor progression through regulation of epithelial and stromal cell signaling. Dysfunction of the pathway can lead to carcinoma progression and metastasis. To gain insight into the stromal role of the TGF-β pathway in breast cancer, we performed laser capture microdissection (LCM) from breast cancer patients and reduction mammoplasty patients. Microdissected tumor stroma and normal breast stroma were examined for gene expression. Expression of the TGF-β type III receptor (TGFBR3) was greatly decreased in the tumor stroma compared to control healthy breast tissue. These results demonstrated a 44-fold decrease in TGFBR3 mRNA in tumor stroma in comparison to control tissue. We investigated publicly available databases, and have identified that TGFBR3 mRNA levels are decreased in tumor stroma. We next investigated fibroblast cell lines derived from cancerous and normal breast tissue and found that in addition to mRNA levels, TβRIII protein levels were significantly reduced. Having previously identified that cancer-associated fibroblasts secrete greater levels of tumor promoting cytokines, we investigated the consequences of soluble-TβRIII (sTβRIII) on fibroblasts. Fibroblast conditioned medium was analyzed for 102 human secreted cytokines and distinct changes in response to sTβRIII were observed. Next, we used the fibroblast-conditioned medium to stimulate human monocyte cell line THP-1. These results indicate a distinct transcriptional response depending on sTβRIII treatment and whether it was derived from normal or cancerous breast tissue. We conclude that the effect of TβRIII has distinct roles not only in cancer-associated fibroblasts but that sTβRIII has distinct paracrine functions in the tumor microenvironment. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
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Open AccessArticle Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90
Received: 21 December 2015 / Revised: 25 July 2016 / Accepted: 3 August 2016 / Published: 24 August 2016
Cited by 2 | PDF Full-text (2871 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix; Methods: We isolated CAF from prostate cancer patients of Gleason Score 6–10 and confirmed their cancer-promoting activity
[...] Read more.
Background: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix; Methods: We isolated CAF from prostate cancer patients of Gleason Score 6–10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay; Results: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF; Conclusions: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
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Review

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Open AccessReview Seed-in-Soil: Pancreatic Cancer Influenced by Tumor Microenvironment
Received: 29 June 2017 / Revised: 18 July 2017 / Accepted: 18 July 2017 / Published: 21 July 2017
Cited by 1 | PDF Full-text (478 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic ductal adenocarcinoma is a fatal malignancy with a five-year survival rate lower than 7%, and most patients dying within six months of diagnosis. The factors that contribute to the aggressiveness of the disease include, but are not limited to: late diagnosis, prompt
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Pancreatic ductal adenocarcinoma is a fatal malignancy with a five-year survival rate lower than 7%, and most patients dying within six months of diagnosis. The factors that contribute to the aggressiveness of the disease include, but are not limited to: late diagnosis, prompt metastasis to adjacent vital organs, poor response, and resistance to anticancer treatments. This malignancy is uniquely associated with desmoplastic stroma that accounts for 80% of tumor mass. Understanding the biology of stroma can aid the discovery of innovative strategies for eradicating this lethal cancer in the future. This review highlights the critical components in the stroma and how they interact with the cancer cells to convey the devastating tumor progression. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
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Open AccessReview Breast Cancer-Associated Fibroblasts: Where We Are and Where We Need to Go
Received: 3 December 2015 / Revised: 12 January 2016 / Accepted: 20 January 2016 / Published: 27 January 2016
Cited by 24 | PDF Full-text (251 KB) | HTML Full-text | XML Full-text
Abstract
Cancers are heterogeneous tissues comprised of multiple components, including tumor cells and microenvironment cells. The tumor microenvironment has a critical role in tumor progression. The tumor microenvironment is comprised of various cell types, including fibroblasts, macrophages and immune cells, as well as extracellular
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Cancers are heterogeneous tissues comprised of multiple components, including tumor cells and microenvironment cells. The tumor microenvironment has a critical role in tumor progression. The tumor microenvironment is comprised of various cell types, including fibroblasts, macrophages and immune cells, as well as extracellular matrix and various cytokines and growth factors. Fibroblasts are the predominant cell type in the tumor microenvironment. However, neither the derivation of tissue-specific cancer-associated fibroblasts nor markers of tissue-specific cancer-associated fibroblasts are well defined. Despite these uncertainties it is increasingly apparent that cancer-associated fibroblasts have a crucial role in tumor progression. In breast cancer, there is evolving evidence showing that breast cancer-associated fibroblasts are actively involved in breast cancer initiation, proliferation, invasion and metastasis. Breast cancer-associated fibroblasts also play a critical role in metabolic reprogramming of the tumor microenvironment and therapy resistance. This review summarizes the current understanding of breast cancer-associated fibroblasts. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
Open AccessReview Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth
Cancers 2015, 7(4), 2443-2458; https://doi.org/10.3390/cancers7040902
Received: 23 September 2015 / Revised: 17 November 2015 / Accepted: 7 December 2015 / Published: 11 December 2015
Cited by 76 | PDF Full-text (719 KB) | HTML Full-text | XML Full-text
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
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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. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
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Open AccessReview Direct Interaction between Carcinoma Cells and Cancer Associated Fibroblasts for the Regulation of Cancer Invasion
Cancers 2015, 7(4), 2054-2062; https://doi.org/10.3390/cancers7040876
Received: 2 September 2015 / Revised: 30 September 2015 / Accepted: 12 October 2015 / Published: 14 October 2015
Cited by 21 | PDF Full-text (666 KB) | HTML Full-text | XML Full-text
Abstract
The tumor stroma acts as an essential microenvironment of the cancer cells, which includes many different types of non-cancerous cells and the extracellular matrix (ECM). Stromal fibroblasts (SFs) are the major cellular constituents of the tumor stroma and are often called cancer-associated fibroblasts
[...] Read more.
The tumor stroma acts as an essential microenvironment of the cancer cells, which includes many different types of non-cancerous cells and the extracellular matrix (ECM). Stromal fibroblasts (SFs) are the major cellular constituents of the tumor stroma and are often called cancer-associated fibroblasts (CAFs). They are often characterized by α-smooth muscle actin (αSMA) expression, which is indicative of the myofibroblast phenotype and strong contractility. These characteristics contribute to the remodeling and stiffening of the stromal ECM, thereby offering an appropriate field for cancer cell invasion. Importance of the tumor stroma in cancer progression has recently been highlighted. Moreover, several reports suggest that stromal fibroblasts interact with adjacent cancer cells through soluble factors, exosomes, or direct cell-cell adhesion to promote cancer cell invasion. In this review, current models of the regulation of cancer cell invasion by surrounding fibroblasts are summarized, including our recent work on the interaction between stromal fibroblasts and scirrhous gastric carcinoma (SGC) cells by using a three-dimensional (3D) culture system. Further mechanistic insights into the roles of the interaction between cancer cells and stromal fibroblasts in cancer invasion will be required to identify novel molecular targets for preventing cancer cell invasion. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
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Open AccessReview The Mesothelial Origin of Carcinoma Associated-Fibroblasts in Peritoneal Metastasis
Cancers 2015, 7(4), 1994-2011; https://doi.org/10.3390/cancers7040872
Received: 7 August 2015 / Revised: 14 September 2015 / Accepted: 23 September 2015 / Published: 29 September 2015
Cited by 12 | PDF Full-text (655 KB) | HTML Full-text | XML Full-text
Abstract
Solid tumors are complex and unstructured organs that, in addition to cancer cells, also contain other cell types. Carcinoma-associated fibroblasts (CAFs) represent an important population in the tumor microenviroment and participate in several stages of tumor progression, including cancer cell migration/invasion and metastasis.
[...] Read more.
Solid tumors are complex and unstructured organs that, in addition to cancer cells, also contain other cell types. Carcinoma-associated fibroblasts (CAFs) represent an important population in the tumor microenviroment and participate in several stages of tumor progression, including cancer cell migration/invasion and metastasis. During peritoneal metastasis, cancer cells detach from the primary tumor, such as ovarian or gastrointestinal, disseminate through the peritoneal fluid and colonize the peritoneum. Tumor cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity, then colonizing the submesothelial compact zone where CAFs accumulate. CAFs may derive from different sources depending on the surrounding metastatic niche. In peritoneal metastasis, a sizeable subpopulation of CAFs originates from MCs through a mesothelial-to-mesenchymal transition (MMT), which promotes adhesion, invasion, vascularization and subsequent tumor growth. The bidirectional communication between cancer cells and MC-derived CAFs via secretion of a wide range of cytokines, growth factors and extracellular matrix components seems to be crucial for the establishment and progression of the metastasis in the peritoneum. This manuscript provides a comprehensive review of novel advances in understanding how peritoneal CAFs provide cancer cells with a supportive microenvironment, as well as the development of future therapeutic approaches by interfering with the MMT in the peritoneum. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
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Other

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Open AccessFeature PaperCase Report Acute Myeloid Leukemia with Isolated Trisomy 19 Associated with Diffuse Myelofibrosis and Osteosclerosis
Cancers 2015, 7(4), 2459-2465; https://doi.org/10.3390/cancers7040903
Received: 8 September 2015 / Revised: 9 November 2015 / Accepted: 7 December 2015 / Published: 14 December 2015
PDF Full-text (695 KB) | HTML Full-text | XML Full-text
Abstract
Primary myelofibrosis (PMF), per WHO criteria, is a clonal myeloproliferative neoplasm that usually presents with a proliferation of granulocytic and megakaryocytic lineages with an associated fibrous deposition and extramedullary hematopoiesis. The bone marrow histologic findings of this disorder are typically characterized by the
[...] Read more.
Primary myelofibrosis (PMF), per WHO criteria, is a clonal myeloproliferative neoplasm that usually presents with a proliferation of granulocytic and megakaryocytic lineages with an associated fibrous deposition and extramedullary hematopoiesis. The bone marrow histologic findings of this disorder are typically characterized by the presence of myeloid metaplasia with an associated reactive fibrosis, angiogenesis, and osteosclerosis. However, marked myelofibrosis is not solely confined to PMF and may also be associated with other conditions including but not limited to acute megakaryoblastic leukemias (FAB AML-M7). Here, we describe a rare case of a non-megakaryoblastic acute myeloid leukemia with marked myelofibrosis with osteosclerosis and an isolated trisomy 19. A 19-year-old male presented with severe bone pain of one week duration with a complete blood cell count and peripheral smear showing a mild anemia and occasional circulating blasts. A follow up computed tomography (CT) scan showed diffuse osteosclerosis with no evidence of hepatosplenomegaly or lymphadenopathy. Subsequently, the bone marrow biopsy showed markedly sclerotic bony trabeculae and a hypercellular marrow with marked fibrosis and intervening sheets of immature myeloid cells consistent with myeloblasts with monocytic differentiation. Importantly, these myeloblasts were negative for megakaryocytic markers (CD61 and vWF), erythroid markers (hemoglobin and E-cadherin), and lymphoid markers (CD3, CD19, and TdT). Metaphase cytogenetics showed an isolated triosomy 19 with no JAK2 V617F mutation. The patient was treated with induction chemotherapy followed by allogenic hematopoietic stem cell transplantation which subsequently resulted in a rapid resolution of bone marrow fibrosis, suggesting graft-anti-fibrosis effect. This is a rare case of a non-megakaryoblastic acute myeloid leukemia with myelofibrosis and osteosclerosis with trisomy 19 that may provide insights into the prognosis and therapeutic options of future cases. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
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