Novel signatures of cancer‐associated fibroblasts

Bozóky, Benedek; Savchenko, Andrii; Csermely, Péter; Korcsmáros, Tamás; Dúl, Zoltán; Pontén, Fredrik; Szekeres, L.; Klein, George

doi:10.1002/ijc.28035

Cited by 45 publications

(37 citation statements)

References 46 publications

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“…In addition, PLOD2 expression is enhanced in various types of cancers (e.g. glioma, bone, cervical, and liver) either or not directly caused by cytokines such as TGF␤1, and is strongly linked to the progression of these diseases likely by affecting cross-links of collagen that surrounds these tumors (45)(46)(47)(48)(49). Therefore, dissecting the downstream pathway of TGF␤1-mediated PLOD2 regulation is of fundamental interest to develop strategies that can tackle a wide range of scarring-related pathologies.…”

Section: Discussionmentioning

confidence: 99%

Procollagen Lysyl Hydroxylase 2 Expression Is Regulated by an Alternative Downstream Transforming Growth Factor β-1 Activation Mechanism

Gjaltema

Rond

Rots

et al. 2015

Journal of Biological Chemistry

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Background: PLOD2 expression and subsequent collagen pyridinoline cross-links are induced in fibrotic tissues by TGF␤1. Results: TGF␤1 induces changes to histone modifications. SP1 and SMAD3 but not P300/CBP are responsible for PLOD2 induction. Conclusion: SMAD3 regulates TGF␤1-induced PLOD2 expression via histone-modifying enzymes other than the currently known downstream effectors. Significance: Unraveling PLOD2 transcriptional regulation would provide new ways to interfere in fibrotic processes.

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Section: Discussionmentioning

confidence: 99%

Procollagen Lysyl Hydroxylase 2 Expression Is Regulated by an Alternative Downstream Transforming Growth Factor β-1 Activation Mechanism

Gjaltema

Rond

Rots

et al. 2015

Journal of Biological Chemistry

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“…expressed in cancer-associated stroma and not in normal stroma (15). Four of these markers, DLG1, ROCK2, ARHGAP31, and ARHGAP26, are linked to Rho GTPase signaling.…”

Section: Significancementioning

confidence: 99%

RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo

Alkasalias

Alexeyenko

Hennig

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins overexpressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumorinhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of α-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.Rho GTPases | RhoA | cancer-associated fibroblasts | tumor-inhibitory capacity | cytoskeleton

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“…In tumor microenvironment, cancer-associated fibroblasts have an important role in tumor-stroma interaction and could affect prognosis [3-7]. However, there are no specific markers of cancer-associated fibroblasts that have been proven to be related with tumor prognosis.…”

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confidence: 99%

Overexpression of POSTN in Tumor Stroma Is a Poor Prognostic Indicator of Colorectal Cancer

Bae

Wen

et al. 2017

J Pathol Transl Med

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BackgroundTumor microenvironment has recently drawn attention in that it is related with tumor prognosis. Cancer-associated fibroblast also plays a critical role in cancer invasiveness and progression in colorectal cancers. Periostin (POSTN), originally identified to be expressed in osteoblasts and osteoblast-derived cells, is expressed in cancer-associated fibroblasts in several tissue types of cancer. Recent studies suggest an association between stromal overexpression of POSTN and poor prognosis of cancer patients. MethodsWe analyzed colorectal cancer cases for their expression status of POSTN in tumor stroma using immunohistochemistry and correlated the expression status with clinicopathological and molecular features. ResultsHigh level of POSTN expression in tumor stroma was closely associated with tumor location in proximal colon, infiltrative growth pattern, undifferentiated histology, tumor budding, luminal necrosis, and higher TNM stage. High expression status of POSTN in tumor stroma was found to be an independent prognostic parameter implicating poor 5-year cancer-specific survival and 5-year progression-free survival. ConclusionsOur findings suggest that POSTN overexpression in tumor stroma of colorectal cancers could be a possible candidate marker for predicting poor prognosis in patients with colorectal cancers.

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Novel signatures of cancer‐associated fibroblasts

Cited by 45 publications

References 46 publications

Procollagen Lysyl Hydroxylase 2 Expression Is Regulated by an Alternative Downstream Transforming Growth Factor β-1 Activation Mechanism

Procollagen Lysyl Hydroxylase 2 Expression Is Regulated by an Alternative Downstream Transforming Growth Factor β-1 Activation Mechanism

RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo

Overexpression of POSTN in Tumor Stroma Is a Poor Prognostic Indicator of Colorectal Cancer

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