Head and neck squamous cancer stromal fibroblasts produce growth factors influencing phenotype of normal human keratinocytes

Strnad, Hynek; Lacina, Lukáš; Kolář, Michal; Čada, Zdeněk; Vlček, Čestmı́r; Dvořánková, Barbora; Betka, Jan; Plzák, Jan; Chovanec, Martin; Šáchová, Jana; Valach, Jaroslav; Urbanová, Markéta; Smetana, Karel

doi:10.1007/s00418-009-0661-6

Cited by 47 publications

(40 citation statements)

References 49 publications

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“…Our results from head and neck and esophageal squamous cell carcinomas agree with previous findings. 30,40,41 In addition to these results, the immunohistochemical analysis of BMP4 protein expression in tumor samples has only been performed in colorectal, ovarian, gastric, renal and hepatocellular carcinomas as well as in a few samples of melanoma. In colorectal and gastric cancers, BMP4 expression had been identified in the majority of the samples, but strong expression was detected only in a minority, which resembled the staining pattern we also detected.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 4 expression in multiple normal and tumor tissues reveals its importance beyond development

Alarmo¹,

Huhtala

Korhonen

et al. 2013

Modern Pathology

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Bone morphogenetic proteins (BMPs) are extracellular signaling molecules that belong to the transforming growth factor b (TGFb) superfamily and are known to regulate cell proliferation, differentiation and motility, especially during development. BMP4 has an indispensable role in vertebrate development while limited information on BMP4 expression and function exists in adult tissues. Nevertheless, its contribution to cancer development and progression has gained increasing interest in recent years. Functional studies, especially in breast cancer, have implicated BMP4 both in inhibition of cell proliferation and in promotion of cell migration and invasion. To gain an insight into the function of BMP4 in normal and cancer tissues, BMP4 protein expression levels were analyzed by immunohistochemistry in 34 different normal organs/tissues, 34 different tumor types and finally in 486 breast cancer samples where possible associations between BMP4 and clinicopathological parameters were statistically evaluated. In over 20% of normal and malignant tissues, BMP4 was expressed at high level. Strong expression was observed particularly in some normal epithelial cells, such as bladder and stomach, and in squamous cell carcinomas. In breast cancer, strong BMP4 expression was detected in 25% of patients, and was associated with low proliferation index and increased frequency of tumor recurrence. Taken together, BMP4 is expressed in a subset of normal adult tissues and is likely to contribute to tissue homeostasis. However, in tumors, BMP4 expression levels vary considerably, implying diverse roles in different tumor types. This role is biphasic in breast cancer as BMP4 expression is linked to reduced proliferation and increased recurrence, thus corroborating our previous in-vitro functional data.

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 4 expression in multiple normal and tumor tissues reveals its importance beyond development

Alarmo¹,

Huhtala

Korhonen

et al. 2013

Modern Pathology

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show abstract

“…We employed fibroblasts isolated from cutaneous basal cell carcinoma, which induced expression of keratin 19 in co-cultured normal keratinocytes (Lacina et al 2007b;Szabo et al 2011), squamous cell carcinoma of the oral cavity (Lacina et al 2007a;Strnad et al 2010), cutaneous malignant melanoma, and skin metastasis of the breast carcinoma. The influence of these fibroblasts on EM-G3 cells was compared with experiments in which tumor fibroblasts were replaced in co-cultures by normal human dermal fibroblasts, mouse 3T3 fibroblasts, or mouse 3T3 fibroblasts influenced by the fibroblasts from basal cell carcinoma (Szabo et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Fibroblasts prepared from different types of malignant tumors stimulate expression of luminal marker keratin 8 in the EM-G3 breast cancer cell line

Dvořánková

Szabó

Lacina

et al. 2012

Histochem Cell Biol

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It is widely recognized that stromal fibroblasts significantly influence biological properties of multiple tumors including breast cancer. However, these epithelial-mesenchymal interactions seem to be essential in tumor biology and it is not fully clear whether this interaction is tumor type-specific or has a more general non-specific character. To elucidate this question, we tested the effect of cancer-associated fibroblasts (CAFs) isolated from different types of tumors (breast cancer skin metastasis, cutaneous basal cell carcinoma and melanoma, squamous cell carcinoma arising from oral cavity mucous membrane) on the EM-G3 breast cancer cell line. The results were compared with control experiments using normal human dermal fibroblasts, 3T3 mouse fibroblasts, and 3T3 fibroblasts influenced by the fibroblasts prepared from the basal cell carcinoma. Our results demonstrated that expression of luminal marker keratin 8 was influenced only by CAFs prepared from any tested tumors. In contrast, all tested types of fibroblasts showed a strong stimulatory effect on the expression of basal/myoepithelial marker keratin 14. The CAFs also elevated the number of cells with positivity for both keratins 8 and 14 that are similar to ductal originated precursor cells. The expression of proliferation marker Ki67 was not influenced by any of the tested fibroblasts. In conclusion, our data indicate that CAFs are able to influence the phenotype of a breast cancer cell line and this effect is based on a tumor type-unspecific mechanism. Finally, a clear functional difference between normal and CAFs was demonstrated.

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“…The raw data (.TIFF image files) was analyzed using beadarray package [31] of the Bioconductor [32] within the R environment (http://www.r-project.org) [33]. The gene set enrichment analysis (GSEA) was performed on gene sets defined by the KEGG pathways [34].…”

Section: Microarray Analysismentioning

confidence: 99%

Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats

et al. 2011

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The effect of metformin therapy on cardiac function and survival in volume-overload model of heart failure in rats Short title: Metformin therapy in volume-overload heart failure in rats A c c e p t e d M a n u s c r i p t Licenced copy. Copying is not permitted, except with prior permission and as allowed by law.© 2011 The Authors Journal compilation © 2011 Portland Press Limited 2 Abstract Aims: Advanced heart failure (HF) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. Antihyperglycemic drug metformin (MET) affects substrate metabolism and its use might be associated with improved outcome in diabetic HF. The aim of the study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Methods: Volume overload HF was induced in male Wistar rats by creating aorto-caval fistula (ACF). Animals were randomized to placebo/MET (300mg/kg/day, 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6-12/group) in advanced HF stage (21 st week). A separate cohort served for survival analysis (n=10-90/group). Results: The ACF group had marked cardiac hypertrophy, increased LVEDP and lung weight confirming decompensated HF, increased circulating free fatty acids (FFA), intraabdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triglyceride content and attenuated myocardial 14 C-glucose and 14 C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum FFA, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival despite reaching therapeutic serum level (2.2 ± 0.7 μg/ml). Conclusion: MET-induced enhancement of myocardial fatty acid oxidation had neutral effect on cardiac function and survival. Recently reported cardioprotective effects of MET may not be universal to all forms of HF and may require AMPK activation or ATP depletion. No increase in mortality on MET supports its safe use in diabetic HF. IntroductionAdvanced heart failure (HF) is characterized not only by a depression of heart mechanical performance but also by altered myocardial metabolism -attenuated expression of fatty acid oxidation genes [1,2] and by diminished oxidation of long chain fatty acids [1,[3][4][5], which may contribute to diminished metabolic flexibility and to energetic deficiency that further promotes worsening of HF [6]. Targeting energetic substrate metabolism might thus serve as a target for novel therapeutic approaches to HF [7,8]. Metformin (MET), a widely used antihyperglycemic drug with insulin-sensitizing properties, could be a suitable candidate for metabolic HF therapy. MET lowers serum glucose by inhibiting liver gluconeogenesis, lowers circulating free...

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Head and neck squamous cancer stromal fibroblasts produce growth factors influencing phenotype of normal human keratinocytes

Cited by 47 publications

References 49 publications

Bone morphogenetic protein 4 expression in multiple normal and tumor tissues reveals its importance beyond development

Bone morphogenetic protein 4 expression in multiple normal and tumor tissues reveals its importance beyond development

Fibroblasts prepared from different types of malignant tumors stimulate expression of luminal marker keratin 8 in the EM-G3 breast cancer cell line

Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats

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