scholarly journals Cancer-Associated Fibroblasts as a Common Orchestrator of Therapy Resistance in Lung and Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 987
Author(s):  
Andreas Domen ◽  
Delphine Quatannens ◽  
Sara Zanivan ◽  
Christophe Deben ◽  
Jonas Van Audenaerde ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Growth Factors ◽  
Cancer Metastasis ◽  
Therapy Resistance ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Novel Therapies ◽  
The Past ◽  
Drug Access

Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors. Thus, they are considered to impede the response to current clinical cancer therapies. Therefore, targeting CAFs to counteract these protumorigenic effects, and overcome the resistance to current therapeutic options, is an appealing and emerging strategy. In this review, we discuss how CAFs affect prognosis and response to clinical therapy and provide an overview of novel therapies involving CAF-targeting agents in lung and pancreatic cancer.

Epithelial-Stromal Interactions in Pancreatic Cancer

2019 ◽  
Vol 81 (1) ◽  
pp. 211-233 ◽  
Author(s):  
Yaqing Zhang ◽  
Howard C. Crawford ◽  
Marina Pasca di Magliano
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Lymphatic Vessels ◽  
Cancer Microenvironment ◽  
Cancer Stroma ◽  
The Past ◽  
Overwhelming Evidence ◽  
Cancer Initiation ◽  
Active Research

Pancreatic cancer is characterized by an extensive fibroinflammatory reaction that includes immune cells, fibroblasts, extracellular matrix, vascular and lymphatic vessels, and nerves. Overwhelming evidence indicates that the pancreatic cancer microenvironment regulates cancer initiation, progression, and maintenance. Pancreatic cancer treatment has progressed little over the past several decades, and the prognosis remains one of the worst for any cancer. The contribution of the microenvironment to carcinogenesis is a key area of research, offering new potential targets for treating the disease. Here, we explore the composition of the pancreatic cancer stroma, discuss the network of interactions between different components, and describe recent attempts to target the stroma therapeutically. We also discuss current areas of active research related to the tumor microenvironment.

Mutant Ras-Expressing Fibroblasts Induce Expansion of Circulating Angio- and Lymphangiogenic Precursor Cells: Potential Role in Tumour Vascularisation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1331-1331
Author(s):  
Robert J. Knight ◽  
Tracey A. O’Brien ◽  
Robert Lindeman ◽  
Alla Dolnikov
Keyword(s):  
Extracellular Matrix ◽  
Growth Factors ◽  
Vascular System ◽  
Ex Vivo ◽  
Tumour Microenvironment ◽  
Precursor Cells ◽  
Ras Signaling ◽  
Cancer Therapies ◽  
Angiogenic Growth Factors ◽  
Extracellular Matrix Components

Abstract Fibroblasts have a prominent role in the initiation, enlargement and metastasis of cancers. Their production of growth factors, chemokines and extracellular matrix facilitate the angiogenic recruitment of endothelial cells and pericytes. The oncogene Ras, known to be frequently mutated in many cancers, has also been shown to promote the expression of pro-angiogenic growth factors, chemokines and extracellular matrix components similar to those of fibroblasts. Here we show that mutant N-ras (N-rasm)/GFP - transduced NIH3T3 fibroblasts act to promote the ex vivo expansion of umbilical cord blood (UCB)-derived primitive endothelial progenitor cells through paracrine mechanisms. Biphasic expansion of both angiogenic and lymphangiogenic precursors was observed although they exhibited different dynamics in their expansion pattern. The first peak of expansion for both types of precursor cells was seen on day 10 with a 69-fold expansion of the CD34+VEGFR2+(endothelial) and a 23-fold expansion of CD34+VEGFR3+(lymphatic) cells co-cultured with media conditioned by N-rasm-transduced 3T3 cells. This compared to a 20-fold and 14-fold expansion respectively, in cells co-cultured with media conditioned by GFP (only)-transduced fibroblasts. Endothelial cell differentiation accounts for the dramatic reduction in the numbers of CD34+VEGFR2+ and CD34+VEGFR3+ precursor cells on day 14 with concomitant expansion of CD34−VEGFR2+ and CD34−VEGFR3+cells. The second peak for the expansion of endothelial precursor cells was seen on day 19 with a 214-fold expansion compared to 28-fold in the control cells. In addition, the expansion of CD14+ VEGFR2+ and CD14+VEGFR3+ cells was observed on days 14 and 19, the later correlated with the expansion of monocytic CD34−CD14+ cells promoted by N-rasm-transduced fibroblasts. The expanded monocytes appear to contribute to the expansion of endothelial and lymphatic precursor cells induced by N-rasm-transduced fibroblasts. We propose that the angiogenic factors secreted by mutant Ras-expressing fibroblasts in a tumour microenvironment promote tumour angiogenesis through the expansion of the circulated endothelial and lymphatic precursor cells. The recruitment of the expanded endothelial and lymphatic cells into the tumour’s vascular system is currently being investigated. We propose that targeting aberrant Ras signaling in tumour fibroblasts may represent an important target for cancer therapies.

Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase

2005 ◽  
Vol 289 (6) ◽  
pp. G1137-G1147 ◽  
Author(s):  
Mouad Edderkaoui ◽  
Peggy Hong ◽  
Eva C. Vaquero ◽  
Jong K. Lee ◽  
Lars Fischer ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Growth Factors ◽  
Nadph Oxidase ◽  
Cancer Cells ◽  
Ros Production ◽  
Oxygen Species ◽  
Pancreatic Cancer Cells ◽  
Ecm Proteins

The extracellular matrix (ECM) facilitates pancreatic cancer cells survival, which is of central importance for pancreatic adenocarcinoma that is highly fibrotic. Here, we show that reactive oxygen species (ROS) mediate the prosurvival effect of ECM in human pancreatic cancer cells. Fibronectin and laminin stimulated ROS production and NADPH oxidase activation in pancreatic cancer cells. Both pharmacological and molecular approaches show that fibronectin stimulated ROS production through activation of NADPH oxidase and NADPH oxidase-independent pathways and that 5-lipoxygenase (5-LO) mediates both these pathways. Analyses of the mechanisms of ROS production by ECM proteins and growth factors indicate that activation of NADPH oxidase (Nox4) is a common mechanism employed both by ECM proteins and growth factors to increase ROS in pancreatic cancer cells. We also found that Nox4 is present in human pancreatic adenocarcinoma tissues and that these tissues display membrane NADPH oxidase activity. ECM proteins and growth factors activate NADPH oxidase through different mechanisms; in contrast to ECM proteins, growth factors activate NADPH oxidase through 5-LO-independent mechanisms. Inhibition of 5-LO or NADPH oxidase with pharmacological inhibitors of these enzymes and with Nox4 or 5-LO antisense oligonucleotides markedly stimulated apoptosis in cancer cells cultured on fibronectin. Our results indicate that ROS generation via 5-LO and downstream NADPH oxidase mediates the prosurvival effect of ECM in pancreatic cancer cells. These mechanisms may play an important role in pancreatic cancer resistance to treatments and thus represent novel therapeutic targets.

scholarly journals Involvement of Breast Cancer-Associated Fibroblasts in Tumor Development, Therapy Resistance and Evaluation of Potential Therapeutic Strategies

2018 ◽  
Vol 25 (29) ◽  
pp. 3414-3434 ◽  
Author(s):  
Maria Rosaria Ruocco ◽  
Angelica Avagliano ◽  
Giuseppina Granato ◽  
Valeria Imparato ◽  
Stefania Masone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Chemotherapy Resistance ◽  
Tumor Development ◽  
Therapy Resistance ◽  
Therapeutic Strategies ◽  
Activation Process ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancer Patients ◽  
Cancer Management

Breast cancer is the most common cancer in women, which incidence has increased in recent years. It is constituted by very heterogeneous tissue characterized by an abnormal microenvironment regulating tumor progression and providing evasion from cancer therapies. Breast cancer-associated fibroblasts (BCAFs) are the main cell type of breast cancer microenvironment and can represent up to 80% of the tumor mass. In particular, BCAFs induce cancer initiation, proliferation, invasion and metastasis by undergoing an activation process associated with the secretion of growth factors, cytokines, and paracrine interactions. Therapy resistance is the main cause of poor therapeutic results or even failure in breast cancer patients. Despite recent advances in breast cancer management, there is a need for new prognostic markers and novel agents for targeting key signalling pathways to either improve the efficacy of the current therapies, or reduce toxicity. In this view, BCAFs represent markers useful to clinical diagnosis, therapy, and prognosis of breast cancer. This review focuses on the role of BCAFs in cancer, and describes the processes of endocrine/chemotherapy resistance linked to BCAFs action. Moreover, it points to molecules and pathways regulating therapy resistance induced by BCAFs. Finally, potential therapeutic strategies targeting BCAFs and offering new tools in breast cancer therapy are highlighted.

scholarly journals Cellular Heterogeneity of Pancreatic Stellate Cells, Mesenchymal Stem Cells, and Cancer-Associated Fibroblasts in Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3770
Author(s):  
Yoshiaki Sunami ◽  
Johanna Häußler ◽  
Jörg Kleeff
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Extracellular Matrix ◽  
Mesenchymal Stem Cells ◽  
Extracellular Matrix Proteins ◽  
Stellate Cells ◽  
The United States ◽  
Matrix Proteins ◽  
Pancreatic Stellate Cells ◽  
Cancer Associated Fibroblasts

Pancreatic cancer is projected to become the second deadliest cancer by 2030 in the United States, and the overall five-year survival rate stands still at around 9%. The stroma compartment can make up more than 90% of the pancreatic tumor mass, contributing to the hypoxic tumor microenvironment. The dense stroma with extracellular matrix proteins can be a physical and metabolic barrier reducing therapeutic efficacy. Cancer-associated fibroblasts are a source of extracellular matrix proteins. Therefore, targeting these cells, or extracellular matrix proteins, have been considered as therapeutic strategies. However, several studies show that deletion of cancer-associated fibroblasts may have tumor-promoting effects. Cancer-associated fibroblasts are derived from a variety of different cell types, such as pancreatic stellate cells and mesenchymal stem cells, and constitute a diverse cell population consisting of several functionally heterogeneous subtypes. Several subtypes of cancer-associated fibroblasts exhibit a tumor-restraining function. This review article summarizes recent findings regarding origin and functional heterogeneity of tumor-promoting as well as tumor-restraining cancer-associated fibroblasts. A better understanding of cancer-associated fibroblast heterogeneity could provide more specific and personalized therapies for pancreatic cancer patients in the future.

scholarly journals Immunotherapy in pancreatic cancer treatment: a new frontier

2016 ◽  
Vol 10 (1) ◽  
pp. 168-194 ◽  
Author(s):  
Komal Thind ◽  
Leslie J. Padrnos ◽  
Ramesh K. Ramanathan ◽  
Mitesh J. Borad
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Tumor ◽  
Standard Of Care ◽  
Current Treatment ◽  
Novel Therapies ◽  
Potential Treatment ◽  
The Past ◽  
New Frontier ◽  
Resistance To Chemotherapy

Pancreatic cancer is a highly aggressive and lethal cancer characterized by high invasiveness, local and extensive dissemination at time of diagnosis and resistance to treatment. Few therapies have shown efficacy in the past and even standard of care therapies yield only modest improvements in the mortality of patients with advanced or metastatic disease. Efforts have been undertaken to study the pancreatic tumor microenvironment and have established its complex and immunosuppressive nature which could explain the high resistance to chemotherapy. Novel therapies targeting the tumor microenvironment with an aim to decrease this resistance, improve immune tolerance and increase the efficacy of the current treatment have shown some promising preliminary results in preclinical and clinical trials. We review the current advances in the field of immunotherapy and their effectiveness as a potential treatment strategy in the pancreatic cancer.

scholarly journals Diversity and Biology of Cancer-Associated Fibroblasts

2021 ◽  
Vol 101 (1) ◽  
pp. 147-176 ◽  
Author(s):  
Giulia Biffi ◽  
David A. Tuveson
Keyword(s):  
Cancer Cell ◽  
Therapy Resistance ◽  
The Body ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Anti Cancer ◽  
Cancer Cell Survival ◽  
Epithelial Compartment ◽  
Cancer Types ◽  
Immune Exclusion

Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.

Fibroblastic FAK controls pancreatic cancer metastasis by enhancing extracellular matrix remodeling

Pancreatology ◽  
2017 ◽  
Vol 17 (3) ◽  
pp. S19
Author(s):  
Christine Jean ◽  
Emilie Decaup ◽  
Sonia Zaghdoudi ◽  
Remi Samain ◽  
Stephanie Cassant-Sourdy ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Cancer Metastasis ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling

scholarly journals Impact of the Prolymphangiogenic Crosstalk in the Tumor Microenvironment on Lymphatic Cancer Metastasis

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Simona L. Schlereth ◽  
Nasrin Refaian ◽  
Sandra Iden ◽  
Claus Cursiefen ◽  
Ludwig M. Heindl
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Cancer Associated Fibroblasts ◽  
Therapeutic Approaches ◽  
Early Step ◽  
New Therapeutic Approaches

Lymphangiogenesis is a very early step in lymphatic metastasis. It is regulated and promoted not only by the tumor cells themselves, but also by cells of the tumor microenvironment, including cancer associated fibroblasts, mesenchymal stem cells, dendritic cells, or macrophages. Even the extracellular matrix as well as cytokines and growth factors are involved in the process of lymphangiogenesis and metastasis. The cellular and noncellular components influence each other and can be influenced by the tumor cells. The knowledge about mechanisms behind lymphangiogenesis in the tumor microenvironmental crosstalk is growing and offers starting points for new therapeutic approaches.

scholarly journals Expression and Role of Heparan Sulfated Proteoglycans in Pancreatic Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Simone Furini ◽  
Chiara Falciani
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Growth Factors ◽  
Cancer Genomics ◽  
Altered Expression ◽  
Normal Tissues ◽  
Unfavourable Prognosis ◽  
Poor Outcomes ◽  
Sulfated Proteoglycans

Pancreatic cancer is a lethal condition with poor outcomes and an increasing incidence. The unfavourable prognosis is due to the lack of early symptoms and consequent late diagnosis. An effective method for the early diagnosis of pancreatic cancer is therefore sought by many researchers in the field. Heparan sulfated proteoglycan-related genes are often expressed differently in tumors than in normal tissues. Alteration of the tumor microenvironment is correlated with the ability of heparan sulfated proteoglycans to bind cytokines and growth factors and eventually to influence tumor progression. Here we discuss the importance of glypicans, syndecans, perlecan and extracellular matrix modifying enzymes, such as heparanases and sulfatases, as potential diagnostics in pancreatic cancer. We also ran an analysis on a multidimensional cancer genomics database for heparan sulfated proteoglycan-related genes, and report altered expression of some of them.

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