Stromal fibroblasts synergize with hypoxic oxidative stress to enhance melanoma aggressiveness

Comito, Giuseppina; Giannoni, Elisa; Gennaro, Paola Di; Segura, Coral Pons; Gerlini, Gianni; Chiarugi, Paola

doi:10.1016/j.canlet.2012.04.025

Cited by 47 publications

(47 citation statements)

References 46 publications

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“…One of the soluble factors secreted by CAFs is exosomes, which promote breast cancer cell motility via Wnt-planar cell polarity signaling (22). Furthermore, activated fibroblasts addicted to hypoxia secrete several cytokines, which increase the invasiveness of melanoma cells and are active players in attracting melanoma cells to different locations (23). In agreement with our study, Cheng et al has already shown that p53 attenuates the motility of PC3 tumor cells by inducing the expression of GDF-15 (24).…”

Section: Discussionsupporting

confidence: 90%

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Alkasalias

Flaberg

Kashuba

et al. 2014

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

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Normal human and murine fibroblasts can inhibit proliferation of tumor cells when cocultured in vitro. The inhibitory capacity varies depending on the donor and the site of origin of the fibroblast. We showed previously that effective inhibition requires formation of a morphologically intact fibroblast monolayer before seeding of the tumor cells. Here we show that inhibition is extended to motility of tumor cells and we dissect the factors responsible for these inhibitory functions. We find that inhibition is due to two different sets of molecules: (i) the extracellular matrix (ECM) and other surface proteins of the fibroblasts, which are responsible for contact-dependent inhibition of tumor cell proliferation; and (ii) soluble factors secreted by fibroblasts when confronted with tumor cells (confronted conditioned media, CCM) contribute to inhibition of tumor cell proliferation and motility. However, conditioned media (CM) obtained from fibroblasts alone (nonconfronted conditioned media, NCM) did not inhibit tumor cell proliferation and motility. In addition, quantitative PCR (Q-PCR) data show upregulation of proinflammatory genes. Moreover, comparison of CCM and NCM with an antibody array for 507 different soluble human proteins revealed differential expression of growth differentiation factor 15, dickkopf-related protein 1, endothelial-monocyteactivating polypeptide II, ectodysplasin A2, Galectin-3, chemokine (C-X-C motif) ligand 2, Nidogen1, urokinase, and matrix metalloproteinase 3.tumor microenvironment | cancer-associated fibroblast | motility | extracellular matrix | soluble factors T he normal balance between epithelial cells and the surrounding stroma is disrupted during tumor development. Developing preneoplastic cells in the process of escaping from their intrinsic checkpoints that prevent illegitimate cell proliferation also have to overcome the microenvironmental forces that maintain the integrity of the normal tissue architecture. It is becoming increasingly clear that the normal microenvironment can restrict cancer development and progression (1-3). Inhibition of tumor cell growth by normal fibroblasts is one measurable manifestation of this multicomponential control. Part of this process is reflected by the ability of the tumor cell to corrupt the surrounding stroma and turn it from restrictive to supportive. The generation of cancer-associated fibroblasts (CAFs) that enhance angiogenesis and support tumor growth and spreading through the release of growth factors and cytokines is a case in point (1-5).We have departed from the observation of Stoker et al. that normal fibroblasts can inhibit the growth of admixed tumor cells upon contact (6). Having confirmed their findings, we have extended such findings into a high throughput microwell system and showed that the strength of the inhibition differs depending on the source of the fibroblasts. Moreover, such inhibition is contact dependent as well as requires an intact fibroblast monolayer (7, 8).Here we report the surprising finding that the inhi...

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Section: Discussionsupporting

confidence: 90%

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Alkasalias

Flaberg

Kashuba

et al. 2014

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

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“…(Lacina et al, 2007b). Data presented in this study demonstrate that MAF are able to influence not only melanoma cells (Comito et al, 2012;Kodet et al, 2013) but also keratinocytes. Similarly, melanoma cells are also able to influence keratinocytes (Haass et al, 2010;Kodet et al, 2015).…”

Section: Resultssupporting

confidence: 51%

“…Melanoma cells lack their aggressiveness when they are implemented to early embryo (Kulesa et al, 2006). Moreover, the melanomaassociated fibroblasts (MAF) seem to be able to influence biological properties of melanoma cells including their phenotype (Comito et al, 2012;Kodet et al, 2013). Melanoma cells, similarly to their precursors neural crest cells originated from the hair follicle, are able to significantly influence normal keratinocytes in vitro as well as in vivo (Kodet et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Fibroblasts isolated from the malignant melanoma influence phenotype of normal human keratinocytes

Kučera

Dvořánková

Smetana

et al. 2015

JAB

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Melanoma-associated fibroblastCancer associated fibroblast Epithelial-mesenchymal interaction Vimentin Abbreviations: CAF, cancer associated fibroblast DF, dermal fibroblasts K, high molecular weight keratins K14, keratin type 14 MAF, melanoma-associated fibroblast Vim, vimentin a b s t r a c t Intercellular interactions are able to influence the biological properties of many types of tumors including malignant melanoma. Differentiation pattern of melanoma cells is significantly influenced by the melanoma-associated fibroblasts but the information about interaction of these cells with other important element of melanoma microenvironment,resp. with keratinocytes, is limited. In this, study we tested the effect of fibroblasts isolated from malignant melanoma on phenotype of normal human keratinocytes, especially on their expression of vimentin, a cytoskeletal protein weakly expressed in normal human keratinocytes. The co-culture with normal dermal fibroblasts was used for comparison. The results demonstrated the high expression of vimentin in keratinocytes co-cultured with melanoma-associated fibroblasts compared with those co-cultured with normal dermal fibroblasts. These data suggest participation of melanoma-associated fibroblasts-keratinocyte crosstalk in formation of melanoma niche.

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“…The signature of these two cases (subsequently joined the two fixed cases #6 and #7, Table 1) closely mirrored that of E-MpM but they also had a well-developed stromal component enriched in CAFs expressing SLUG and TWIST, thus supporting the idea that CAFs may elicit the acquisition of stem-like traits and/or favour EMT [53, 54]. No evidence of malignancy of the stromal component was found in any of these cases, but the tumoral cells showed nuclear immunoreactivity when challenged with GATA 4 antibody and retained, albeit decreased, E-cadherin decoration.…”

Section: Discussionmentioning

confidence: 85%

Epithelioid peritoneal mesothelioma: a hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework

et al. 2016

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The aim of this study was to reconsider the biological characteristics of epithelioid malignant peritoneal mesothelioma (E-MpM) in the light of new concepts about epithelial mesenchymal transition and mesenchymal epithelial reverse transition (EMT/MErT) and the role of epigenetic reprogramming in this context. To this end we profiled surgical specimens and derived cells cultures by a number of complementary approaches i.e. immunohistochemistry, immunofluorescence, in situ hybridization, biochemistry, pluripotent stem cell arrays, treatments with cytokines, growth factors and specific inhibitors.The analyses of the surgical specimens showed that i) EZH2 is expressed throughout the spectrum of MpM, ii) that E-MpM (including the high-grade undifferentiated form) are characterised by c-MYC and miRNA 17-5p expression, and iii) that progression to sarcomatoid MpM is dictated by EMT regulators. They also showed that E-MpM expressed c-MET and are enriched in E- and P-cadherins- and VEGFR2-expressing CSCs, thus strongly supporting a role for MErT reprogramming in endowing E-MpM tumour cells with stemness and plasticity, and hence with a drug resistant phenotype. The cell culture-based experiments confirmed the stemness traits and plasticity of E-MpM, and support the view that EZH2 is a druggable target in this tumor.

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Stromal fibroblasts synergize with hypoxic oxidative stress to enhance melanoma aggressiveness

Cited by 47 publications

References 46 publications

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Fibroblasts isolated from the malignant melanoma influence phenotype of normal human keratinocytes

Epithelioid peritoneal mesothelioma: a hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework

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