Transforming growth factor-β1 induces tumor stroma and reduces tumor infiltrate in cervical cancer

Hazelbag, Suzanne; Gorter, Arko; Kenter, Gemma G.; Broek, Lambert van den; Fleuren, G. J.

doi:10.1053/hupa.2002.130109

Cited by 65 publications

(56 citation statements)

References 46 publications

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“…26 This implies that the LHC are remnants of a resident population initially present in the epithelial layer of the cervix. 27 Monocytes are known to be attracted to the tumor site by certain chemokines.…”

Section: Discussionmentioning

confidence: 99%

Role of tumor‐derived proinflammatory cytokines GM‐CSF, TNF‐α, and IL‐12 in the migration and differentiation of antigen‐presenting cells in cervical carcinoma

Zijlmans

Fleuren

Baelde

et al. 2006

Cancer

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BACKGROUND.Proinflammatory cytokines are important in modifying the activity, differentiation, and migration of antigen‐presenting cells and may influence the survival of cancer patients. The study assessed whether GM‐CSF, TNF‐α, and IL‐12, produced by cervical cancer cells, are important for the activity, differentiation, and migration of antigen‐presenting cells.METHODS.In 90 patients with cervical carcinoma the number of monocytes/tumor‐associated macrophages (TAM), mature dendritic cells (DC), and Langerhans cells (LHC) was determined using immunohistochemistry. An RNA in situ hybridization technique was used to measure the expression level of GM‐CSF, TNF‐α, IL‐12p35, and IL‐12p40.RESULTS.TAM were detected intraepithelial as well as in the stroma of the tumor. LHC were only detected intraepithelial and mature DC only in the tumor stroma. The number of TAM correlated positively with the number of mature DC. The expression levels of GM‐CSF and TNF‐α correlated positively with the number of TAM and DC. TNF‐α showed a negative correlation with the number of LHC. A significant correlation between the expression of functional IL‐12 (IL‐12p40) and stromal TAM was found. The expression of GM‐CSF, TNF‐α, and IL‐12p40 did not correlate significantly with disease‐free survival. However, high IL‐12p40 expression was associated with a favorable cumulative overall survival.CONCLUSIONS.The results suggest that GM‐CSF as well as TNF‐α, produced by cervical carcinoma cells, may play a role in the differentiation of monocytes into mature DC. Furthermore, TNF‐α may influence the migration of LHC from the tumor. Cancer 2007;109:556–565. © 2007 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Role of tumor‐derived proinflammatory cytokines GM‐CSF, TNF‐α, and IL‐12 in the migration and differentiation of antigen‐presenting cells in cervical carcinoma

Zijlmans

Fleuren

Baelde

et al. 2006

Cancer

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“…Standard immunohistochemical staining was performed as described previously. 14 In the case of immunohistochemistry with the Smad2, P-Smad2 and Smad4 antibodies, antigen retrieval was performed with 0.01 M citrate buffer. mAb directed against Smad4 (clone B8; dilution 1:200; Santa Cruz, Santa Cruz, CA, USA), 15 P-Smad2 (clone 138D4, dilution 1:50; Cell Signaling Technology, Beverly, CA, USA) 16 and p21 (clone EA10, dilution 1:200; Calbiochem, San Diego, CA, USA) 17 and a polyclonal antibody against Smad2 (dilution 1:200; Santa Cruz) 18 were used.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival

et al. 2008

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Alterations in transforming growth factor-b signaling, due to a decrease in Smad2 and especially Smad4 expression, has primarily been reported in pancreatic and colorectal cancers, although loss of the chromosomal region 18q21.1, containing the loci of Smad2 and Smad4, is among the most frequent molecular alterations in cervical cancer. The aim of our study was to investigate whether decreased Smad2 and Smad4 protein expression in primary cervical cancers is associated with molecular alterations at 18q21.1, mutations in the functional domains of Smad2 and Smad4 or hypermethylation, and to assess the biological relevance of decreased Smad2 and Smad4 expression. Subsequently, Smad2, Smad4 and p21 protein expression was determined by immunohistochemistry in 117 primary cervical carcinomas, assembled in a tissue array. Smad signaling was shown to be associated with p21 mRNA expression. All the tumors expressed Smad2 or Smad4. Weak cytoplasmic Smad2 or weak cytoplasmic Smad4 expression could not be attributed to loss of heterozygosity at 18q21.1. Despite weak/moderate Smad2 expression and absent nuclear Smad4 expression, the coding regions of the functional MH1 and MH2 domains of Smad2 and Smad4 were unchanged, as assessed by sequence analysis. The Smad4 promoter region was unmethylated in tumor samples with weak/moderate cytoplasmic Smad4 expression. Remarkably, both weak cytoplasmic Smad4 expression and absent nuclear Smad4 expression significantly correlated with poor disease-free (P ¼ 0.003 and P ¼ 0.003, respectively) and overall 5-year survival (P ¼ 0.003 and P ¼ 0.010, respectively). Our findings support the hypothesis that Smad4 is a target molecule for functional inactivation in cervical cancer.

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“…Antigen retrieval was performed, if necessary, and sections were rinsed in phosphate-buffered saline (PBS) followed by an incubation with 1% w/v bovine serum albumin (BSA) in PBS. Subsequently, sections were stained for CD68 , anb6 (Hazelbag et al, 2007), fibronectin (Hazelbag et al, 2002), VEGF-A, bFGF, matrix metalloproteinase (MMP)-2 (Sier et al, 2006), CD31 and CD105 (see Table 2 for characteristics of the primary antibodies). All antibodies were diluted in 1% BSA in PBS.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Furthermore, TGF-b 1 is known to induce VEGF expression (McMahon et al, 2006). Earlier we have reported on the expression of TGF-b 1 , plasminogen activator inhibitor (PAI)-1 and fibronectin (both target gene products of TGF-b 1 ) and avb6 (activator of TGF-b 1 ) in cervical carcinoma (Hazelbag et al, 2002(Hazelbag et al, , 2004(Hazelbag et al, , 2007.…”

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confidence: 99%

Expression of endoglin (CD105) in cervical cancer

et al. 2009

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In this study, we have investigated the role of endoglin (CD105), a regulator of transforming growth factor (TGF)-b 1 signalling on endothelial cells, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF-A) in cervical cancer. We have measured the number and determined the location of both newly formed (CD105-positive) and the overall number of (CD31-positive) blood vessels, and bFGF and VEGF-A expression using immunohistochemistry in 30 cervical carcinoma specimens. Vascular endothelial growth factor-A mRNA expression was determined using RNA-in situ hybridisation. CD105-and CD31-positive vessels and bFGF-and VEGF-A-positive cells were predominantly present in the stroma. The presence of CD105-and CD31-positive vessels in the stroma did neither correlate with the number of VEGF-A-positive cells nor the number of bFGF-positive cells. However, the number of CD105-and CD31-positive vessels was associated with the expression of VEGF-A mRNA in the epithelial cell clusters (P ¼ 0.013 and P ¼ 0.005, respectively). The presence of CD105-positive and CD31-positive vessels was associated with the expression of avb6 (a TGF-b 1 activator; P ¼ 0.013 and P ¼ 0.006, respectively). Clinically, the number of CD105-positive vessels associated with the number of lymph node metastasis (Po0.001). Furthermore, the presence of CD105-positive vessels within the epithelial cell clusters associated with poor disease-free survival (P ¼ 0.007).

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Transforming growth factor-β1 induces tumor stroma and reduces tumor infiltrate in cervical cancer

Cited by 65 publications

References 46 publications

Role of tumor‐derived proinflammatory cytokines GM‐CSF, TNF‐α, and IL‐12 in the migration and differentiation of antigen‐presenting cells in cervical carcinoma

Role of tumor‐derived proinflammatory cytokines GM‐CSF, TNF‐α, and IL‐12 in the migration and differentiation of antigen‐presenting cells in cervical carcinoma

Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival

Expression of endoglin (CD105) in cervical cancer

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