GM-CSF gene expression and protein production in human colorectal cancer cell lines and clinical tumor specimens

Trutmann, Markus; Terracciano, Luigi; Noppen, Christoph; Kloth, Judith; Kaspar, Marlies; Peterli, Ralph; Tondelli, P; Schaefer, Christoph; Zajac, Paul; Heberer, Michael; Spagnoli, Giulio C.

doi:10.1002/(sici)1097-0215(19980729)77:3<378::aid-ijc12>3.0.co;2-4

Cited by 27 publications

(31 citation statements)

References 27 publications

(19 reference statements)

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“…This is in agreement with the previously reported effect of GM-CSF on migration of LHC/DC into organotypic cultures of HPV-transformed keratinocytes. 30 A similar positive correlation between the presence of GM-CSF, TNF-a, and the number of mature DC in breast cancer tissue was reported by Tsuge et al 31 In contrast, Trutmann et al 32 did not report a significant association between expression of GM-CSF and number of mature DC in colorectal cancer. A high level of TNF-a is known to induce migration of LHC to peripheral lymph nodes.…”

Section: Discussionsupporting

confidence: 53%

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: Discussionsupporting

confidence: 53%

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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“…Murine inflammatory monocytes, the CD14 high human blood monocyte counterparts, are known to express CD62L and CCR2, allowing them to enter inflamed skin, but in line with Jackubzick et al (63) they might enter noninflamed peripheral tissues such as skin via hair follicles, as proposed by Nagao et al (65), and differentiate into macrophages, LCs, or remain as circulating monocytes according to the encountered environment. In line with this, sparse studies reported basal GM-CSF synthesis in human and murine skin or colonic mucosa, most predominantly by KCs and fibroblasts (66)(67)(68). Interestingly, Yasmin et al (40) have clearly shown that BMP-7 precedes TGF-b1 during embryonic life, between 8-10 and 9-11 wk estimated gestational age, respectively (69).…”

Section: Discussionmentioning

confidence: 91%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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Langerhans cells (LCs) are epithelial APCs that sense danger signals and in turn trigger specific immune responses. In steady-state, they participate in the maintenance of peripheral tolerance to self-antigens whereas under inflammation LCs efficiently trigger immune responses in secondary lymphoid organs. It has been demonstrated in mice that LC-deprived epithelia are rapidly replenished by short half-life langerin-expressing monocyte-derived LCs (MDLCs). These surrogate LCs are thought to be progressively replaced by langerinhigh LCs arising from self-renewing epithelial precursors of hematopoietic origin. How LCs arise from blood monocytes is not fully understood. Hence, we sought to characterize key factors that induce differentiation of langerinhigh-expressing monocyte-derived Langerhans-like cells. We identified GM-CSF and TGF-β1 as key cytokines to generate langerinhigh-expressing cells but only in serum-free conditions. These cells were shown to express the LC-specific TROP-2 and Axl surface markers and contained Birbeck granules. Surprisingly, E-cadherin was not spontaneously expressed by these cells but required a direct contact with keratinocytes to be stably induced. MDLCs induced stronger allogeneic T cell proliferations but released low amounts of inflammatory cytokines upon TLR stimulation compared with donor-paired monocyte-derived dendritic cells. Immature langerinhigh MDLCs were responsive to MIP-3β/CCL20 and CTAC/CCL27 chemokine stimulations. Finally, we demonstrated that those cells behaved as bona fide LCs when inserted in a three-dimensional rebuilt epithelium by becoming activated upon TLR or UV light stimulations. Collectively, these results prompt us to propose these langerinhigh MDLCs as a relevant model to address LC biology–related questions.

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“…We and others have previously shown that colorectal cancer cells do produce GM-CSF (21,35). Interestingly, colorectal cancer cell lines producing GM-CSF have been suggested to be highly aggressive in vivo (36), possibly because of the activation of macrophages, promoting stromal reactivity.…”

Section: Discussionmentioning

confidence: 95%

GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer

Nebiker

Han

Eppenberger‐Castori

et al. 2014

Clinical Cancer Research

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H-thymidine incorporation. Expression of cytokine genes in colorectal cancer and autologous healthy mucosa was tested by quantitative, real-time PCR. A tumor microarray (TMA) including >1,200 colorectal cancer specimens was stained with GM-CSF-and M-CSF-specific antibodies. Clinicopathological features and overall survival were analyzed.Results: GM-CSF induced CD16 expression in 66% AE 8% of monocytes, as compared with 28% AE 1% in cells stimulated by M-CSF (P ¼ 0.011). GM-CSF but not M-CSF-stimulated macrophages significantly (P < 0.02) inhibited colorectal cancer cell proliferation. GM-CSF gene was expressed to significantly (n ¼ 45, P < 0.0001) higher extents in colorectal cancer than in healthy mucosa, whereas M-CSF gene expression was similar in healthy mucosa and colorectal cancer. Accordingly, IL1b and IL23 genes, typically expressed by M1 macrophages, were expressed to significantly (P < 0.001) higher extents in colorectal cancer than in healthy mucosa. TMA staining revealed that GM-CSF production by tumor cells is associated with lower T stage (P ¼ 0.02), "pushing" growth pattern (P ¼ 0.004) and significantly (P ¼ 0.0002) longer survival in mismatch-repair proficient colorectal cancer. Favorable prognostic effect of GM-CSF production by colorectal cancer cells was confirmed by multivariate analysis and was independent from CD16 þ and CD8 þ cell colorectal cancer infiltration. M-CSF expression had no significant prognostic relevance. Conclusions: GM-CSF production by tumor cells is an independent favorable prognostic factor in colorectal cancer. Clin Cancer Res; 20(12); 3094-106. Ó2014 AACR.

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GM-CSF gene expression and protein production in human colorectal cancer cell lines and clinical tumor specimens

Cited by 27 publications

References 27 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

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer

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