Tumors are unique organs defined by abnormal signaling and context

Radisky, Derek C.; Hagios, Carmen; Bissell, Mina J.

doi:10.1006/scbi.2000.0360

Cited by 152 publications

(113 citation statements)

References 103 publications

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“…Factors secreted from the tumor cells activate local fibroblasts, which in turn secrete increased levels of growth factors, chemokines, ECM proteins, and matrix remodeling enzymes to modify the tumor microenvironment and promote proliferation, survival, invasion, and metastasis of the tumor cells (5,(16)(17)(18). Fibroblasts sense changes in their microenvironment through integrins (19), and form focal adhesion complexes with intracellular molecules that engage the cytoplasmic tyrosine kinases, focal adhesion kinase (FAK) and Src, to activate multiple signaling pathways (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling

Barker

Bird

Lang

et al. 2013

Molecular Cancer Research

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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.

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Section: Introductionmentioning

confidence: 99%

Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling

Barker

Bird

Lang

et al. 2013

Molecular Cancer Research

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“…Our results and others may indicate potential therapeutic targets for treatment of pancreatic cancer aiming at cytokines. 33,42 In summary, the current study demonstrates the potential roles and molecular mechanisms of CypA and CD147 in pancreatic cancer pathogeneses. It also opens up a door for studies of cytokine involvement in pancreatic cancer development.…”

Section: Discussionmentioning

confidence: 66%

Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147

Li¹,

Zhai

Bharadwaj³

et al. 2006

Cancer

141

127

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BACKGROUNDAlthough overexpression of cyclophilin A (CypA) is associated with several types of cancer, its role in pancreatic cancer has not been studied. In this study the expression of CypA and its receptor CD147 on pancreatic cancer was determined as well as the effect of exogenous CypA on pancreatic cancer cell proliferation.METHODSThe expression of CypA and CD147 in human pancreatic cancer cell lines and tissues was determined with real‐time reverse transcriptase polymerase chain reaction (RT‐PCR), Western blot, and immunostaining. Cell proliferation in response to CypA was performed by [3H]thymidine incorporation assay. Phosphorylation of MAPK and cytokine secretion profiles in pancreatic cancer cells were determined by using the Bio‐Plex phosphoprotein assay and cytokine assay.RESULTSPancreatic cancer cell lines expressed significantly higher levels of CypA and CD147 than normal human pancreatic ductal epithelium (HPDE) cells. Expression of CypA and CD147 was also substantially higher in human pancreatic adenocarcinoma tissues than those in normal pancreatic tissues. Addition of exogenous CypA significantly stimulated pancreatic cancer cell proliferation in a dose‐dependent manner and this effect was effectively blocked by pretreatment with anti‐CD147 antibody. In addition, CypA activated ERK1/2 and p38 MAPK signaling pathways and increased the secretion of 2 key cytokines IL‐5 and IL‐17 in Panc‐1 cells.CONCLUSIONSThe expression of CypA and CD147 was significantly increased in both pancreatic cancer cell lines and tissues. Exogenous CypA promotes pancreatic cancer cell growth, which may be mediated through the interaction with CD147 and the activation of ERK1/2 and p38 MAPKs. Cancer 2006. © 2006 American Cancer Society.

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“…However, a tumor is much more than clusters of transformed cells standing alone. Tumor epithelial cells can only thrive in an aberrant microenvironment composed of altered extracellular matrix (ECM) and various non-transformed cells (e.g., fibroblasts, myofibroblasts, leukocytes, and myoepithelial and endothelial cells) that play a role in the initiation and progression of neoplasms [2][3][4][5]. Cross-talk between epithelial and stromal cells is known to be essential for differentiation and development of normal organs and tissues as well as for the growth and progression of tumors [2,6,7].…”

Section: Introductionmentioning

confidence: 99%

Microenvironmental regulation of cancer development

Polyák

2008

Current Opinion in Genetics & Development

295

213

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Numerous studies have demonstrated that the tumor microenvironment not only responds to and supports carcinogenesis, but actively contributes to tumor initiation, progression, and metastasis. During tumor progression all cells composing the tumor undergo phenotypic and epigenetic changes. Paracrine signaling between epithelial and stromal cells is important for the regulation of the proliferation, invasive, angiogenic, and metastatic behavior of cancer cells. Better understanding the molecular mechanisms by which stromal cells exert these effects may open up new venues for cancer therapeutic and preventative interventions.

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Tumors are unique organs defined by abnormal signaling and context

Cited by 152 publications

References 103 publications

Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling

Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling

Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147

Microenvironmental regulation of cancer development

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