The role of the myofibroblast in tumor stroma remodeling

Otranto, Marcela; Sarrazy, Vincent; Bonté, Frédéric; Hinz, Boris; Gabbiani, Giulio; Desmoulière, Alexis

doi:10.4161/cam.20377

Cited by 220 publications

(210 citation statements)

References 279 publications

(343 reference statements)

Supporting

Mentioning

205

Contrasting

Order By: Relevance

“…S1C). These findings suggest that LOXL2 facilitates fibroblast activation and production of a strong fibrous ECM structure in 4T1 tumors, both of which are known to enhance tumor cell invasion and metastasis (32)(33)(34)(35)(36).…”

Section: Inhibition Of Loxl2 Reduces A-sma Expression In 4t1 Orthotopmentioning

confidence: 85%

Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling

Barker

Bird

Lang

et al. 2013

Molecular Cancer Research

View full text Add to dashboard Cite

Cancer-associated fibroblasts enhance cancer progression when activated by tumor cells through mechanisms not yet fully understood. Blocking mammary tumor cell-derived lysyl oxidase-like 2 (LOXL2) significantly inhibited mammary tumor cell invasion and metastasis in transgenic and orthotopic mouse models. Here, we discovered that tumor-derived LOXL2 directly activated stromal fibroblasts in the tumor microenvironment. Genetic manipulation or antibody inhibition of LOXL2 in orthotopically grown mammary tumors reduced the expression of a-smooth muscle actin (a-SMA). Using a marker for reticular fibroblasts, it was determined that expression of a-SMA was localized to fibroblasts recruited from the host tissue. This marker also revealed that the matrix present in tumors with reduced levels of LOXL2 was more scattered compared with control tumors which exhibited matrices with dense, parallel alignments. Importantly, in vitro assays revealed that tumor-derived LOXL2 and a recombinant LOXL2 protein induced fibroblast branching on collagen matrices, as well as increased fibroblast-mediated collagen contraction and invasion of fibroblasts through extracellular matrix. Moreover, LOXL2 induced the expression of a-SMA in fibroblasts grown on collagen matrices. Mechanistically, it was determined that LOXL2 activated fibroblasts through integrinmediated focal adhesion kinase activation. These results indicate that inhibition of LOXL2 in tumors not only reduces tumor cell invasion but also attenuates the activation of host cells in the tumor microenvironment.Implications: These findings reveal new insight into the mechanisms of fibroblast activation, a novel function of LOXL2, and further highlight the importance of generating LOXL2-targeted therapies for the prevention of tumor progression and metastasis.

show abstract

Section: Inhibition Of Loxl2 Reduces A-sma Expression In 4t1 Orthotopmentioning

confidence: 85%

Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling

Barker

Bird

Lang

et al. 2013

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…CAFs have been identified as potent stimulators of cancer metastasis (102,103). They contribute to remodeling of the tumor microenvironment and promote its stiffness mediating a mesenchymal phenotype in epithelial cells by loosing their cell-cell junctions and polarity (104,105). The generation of CAFs by tumor cellderived exosomes has been described in numerous examples.…”

Section: Exosome Mediated Interplay Between Tumor Cells With Fibroblamentioning

confidence: 99%

The Multiple Roles of Exosomes in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

168

133

View full text Add to dashboard Cite

Abstract. Exosomes are important contributors to cellMetastases are responsible for the death of a large majority of cancer patients despite considerable progress in surgical techniques, radiotherapy, chemotherapy and targeted therapies including immuno-therapy (1). A dramatic reduction of metastatic burden has been observed, however, tumor elimination is almost always incomplete. This phenomenon is based on drug resistance, which is due to adaptation of intracellular pathways or on activation of survival-supporting autocrine and paracrine pathways and several secreted factors expressed by drug-sensitive tumor cells after therapy (2). Metastasis can occur through release of cancer cells from the primary tumor into body cavities that holds true for ovarian and CNS tumors, or via hematogeneous and lymphatic vessels of the circulatory system (3). Metastases of some tumors are directed besides to lymph nodes to mainly one type of organ only, such as prostate cancer to the bones, pancreatic cancer and uveal melanoma to the liver, whereas tumors such as melanoma, breast-and lung cancer can colonize several types of organs (3). Tumor cells have been found in the blood of patients with early-stage cancer and in some cases even before the primary tumor has been diagnosed (4, 5). Recently, making use of single-cell expression profiling, it has been shown that early metastatic cells possess a stem-like gene signature and give rise to heterogeneous metastases (6). The metastatic process is characterized by a defined sequence of events (7,8). Initial steps are detachment from the extracellular matrix (ECM), invasion into the surrounding tissue and proteolysis of the basement membrane. After intravasation, survival of circulating tumor cells (CTCs) is achieved by forming clusters, binding to platelets and immune evasion. Subsequently, they arrest in distal microvascular beds and extravasation can be achieved either by migration through intercellular junctions of endothelial cells (EC) or penetration of a single EC (9). CTCs can also colonize their tumors of origin, a process referred to as "tumor self-seeding", selecting for cancer cell populations more aggressive than those present in the primary tumor (10). After extravasation, colonization and outgrowth in the parenchyma of distant organs are the following steps. A common theme of the metastatic process is settlement of disseminated tumor cells (DTCs) into latency (dormancy), which can last from several months to decades (11). It has been observed that DTCs are recruited into pre-metastatic niches that support their survival by interactions with endothelial, myeloid cells, fibroblasts and other types of cells. After adaptation to the host microenvironment and suppression of an anti-tumoral immune response, DTCs are activated by not yet completely resolved mechanisms. Finally their outgrowth is based on an angiogenic switch mediated by pro-angiogenic factors and establishment of a vascular network to support the metabolic demands of colonizing tumor cells (12). In the follo...

show abstract

“…The breach of the epithelial layer is followed by changes that occur in the underlying connective tissue resulting in the loss of tissue homeostasis [1] . Normal wound healing is a well-known phenomenon.…”

Section: Role Of Mfs In Wound Contractionmentioning

confidence: 99%

“…However, interferon-γ, a basic fibroblast growth factor (bFGF), prostaglandin E2, and high cell density inhibit the differentiation of protofibroblasts to MFs [20] . After activation, MFs initiate the synthesis of a new collagencontaining matrix that consists proteoglycans and glycosaminoglycans (highly hydrated molecules) [1,22,24] . They produce tractional forces at the margins for wound contraction, which is known as tractional remodelling [22] .…”

Section: Role Of Mfs In Wound Contractionmentioning

confidence: 99%

“…Oral mucosa comprises stratified squamous epithelium, and its underlying connective tissue harbours various mesenchymal cells such as fibroblasts, endothelial cells, and pericytes [1,2] . These cells and their extracellular matrix (ECM) play pivotal roles in cell differentiation and proliferation during tissue development, wound healing processes, and pathological alterations [2,3] .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation