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Interleukin-27 re-educates intratumoral myeloid cells and down-regulates stemness genes in non-small cell lung cancer.

Airoldi I, Tupone MG, Esposito S, Russo MV, Barbarito G, Cipollone G, Di Carlo E - Oncotarget (2015)

Bottom Line: In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression.Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects.In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Oncology, Istituto "Giannina Gaslini", Genova 16147, Italy.

ABSTRACT
Current therapies for Non-Small Cell Lung Cancer (NSCLC) still fail to significantly increase its survival rate. Here we asked whether Interleukin(IL)-27, which has revealed powerful antitumor activity and is toxicity-free in humans, is a promising therapeutic choice for NSCLC patients. IL-27's effects were tested on Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) cell lines and xenograft models. IL-27Receptor(R) expression was assessed in lung tissues from 78 NSCLC patients. In vitro, IL-27 was ineffective on cancer cell proliferation or apoptosis, but fostered CXCL3/GROγ/MIP2β expression. In vitro and in vivo, IL-27 down-regulated stemness-related genes, namely SONIC HEDGEHOG in AC cells, and OCT4A, SOX2, NOTCH1, KLF4 along with Nestin, SNAI1/SNAIL, SNAI2/SLUG and ZEB1, in SCC cells. In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression. Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects. In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease. Our data suggest that even immunocompromised or advancer NSCLC patients may benefit from IL-27's antitumor properties based on its ability to drive myeloid cells towards antitumor activities, and down-regulate stemness- and EMT-related genes in cancer cells.

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Expression of IFNγ and Down-Modulation of Stemness Genes and EMT-Regulating Transcription Factors by IL-27 in SK-MES Tumors in vivo(A) An evident weakness of the laminin network and a slight, but distinct expression of IFNγ were observed in SK-MES tumors harvested from hrIL-27 treated mice in comparison with control tumors. (X400). (B) In comparison with Calu-6 tumors from control mice, those from hrIL-27-treated mice presented a reduced percentage of cancer cells endowed with a distinct to strong expression of SHH. (X630). (C) In comparison with SK-MES tumors from control mice, those from hrIL-27-treated mice showed a reduced percentage of cancer cells endowed with a distinct to strong expression of OCT4A, SOX2, SOX9, NOTCH1, and KLF4. (OCT4A and SOX9: X400; SOX2, NOTCH1, and KLF4: X630). (D) Expression of Nestin was faint following hrIL-27 treatment, while it was distinct to strong in control tumors. Nuclear expression of SNAI1, SNAI2, and ZEB1 was less frequent in tumors from hrIL-27 treated mice than in control tumors, and the tumor cell surface expression of E-Cadherin was stronger in the former than in the latter. (Nestin: X630; SNAI1, SNAI2, ZEB1, and E-Cadherin: X400).
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Figure 3: Expression of IFNγ and Down-Modulation of Stemness Genes and EMT-Regulating Transcription Factors by IL-27 in SK-MES Tumors in vivo(A) An evident weakness of the laminin network and a slight, but distinct expression of IFNγ were observed in SK-MES tumors harvested from hrIL-27 treated mice in comparison with control tumors. (X400). (B) In comparison with Calu-6 tumors from control mice, those from hrIL-27-treated mice presented a reduced percentage of cancer cells endowed with a distinct to strong expression of SHH. (X630). (C) In comparison with SK-MES tumors from control mice, those from hrIL-27-treated mice showed a reduced percentage of cancer cells endowed with a distinct to strong expression of OCT4A, SOX2, SOX9, NOTCH1, and KLF4. (OCT4A and SOX9: X400; SOX2, NOTCH1, and KLF4: X630). (D) Expression of Nestin was faint following hrIL-27 treatment, while it was distinct to strong in control tumors. Nuclear expression of SNAI1, SNAI2, and ZEB1 was less frequent in tumors from hrIL-27 treated mice than in control tumors, and the tumor cell surface expression of E-Cadherin was stronger in the former than in the latter. (Nestin: X630; SNAI1, SNAI2, ZEB1, and E-Cadherin: X400).

Mentions: Lastly immunohistochemical analyses revealed that the microvascular network of Calu-6 tumors from hrIL-27-treated mice was similar to that of the controls whereas that of SK-MES tumors from hrIL-27-treated mice was clearly impaired (Figure 2C and 2D) (Table 3) in association with a weakened laminin network and a faint, but distinct cancer cell expression of IFNγ (Figure 3A).


Interleukin-27 re-educates intratumoral myeloid cells and down-regulates stemness genes in non-small cell lung cancer.

Airoldi I, Tupone MG, Esposito S, Russo MV, Barbarito G, Cipollone G, Di Carlo E - Oncotarget (2015)

Expression of IFNγ and Down-Modulation of Stemness Genes and EMT-Regulating Transcription Factors by IL-27 in SK-MES Tumors in vivo(A) An evident weakness of the laminin network and a slight, but distinct expression of IFNγ were observed in SK-MES tumors harvested from hrIL-27 treated mice in comparison with control tumors. (X400). (B) In comparison with Calu-6 tumors from control mice, those from hrIL-27-treated mice presented a reduced percentage of cancer cells endowed with a distinct to strong expression of SHH. (X630). (C) In comparison with SK-MES tumors from control mice, those from hrIL-27-treated mice showed a reduced percentage of cancer cells endowed with a distinct to strong expression of OCT4A, SOX2, SOX9, NOTCH1, and KLF4. (OCT4A and SOX9: X400; SOX2, NOTCH1, and KLF4: X630). (D) Expression of Nestin was faint following hrIL-27 treatment, while it was distinct to strong in control tumors. Nuclear expression of SNAI1, SNAI2, and ZEB1 was less frequent in tumors from hrIL-27 treated mice than in control tumors, and the tumor cell surface expression of E-Cadherin was stronger in the former than in the latter. (Nestin: X630; SNAI1, SNAI2, ZEB1, and E-Cadherin: X400).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414147&req=5

Figure 3: Expression of IFNγ and Down-Modulation of Stemness Genes and EMT-Regulating Transcription Factors by IL-27 in SK-MES Tumors in vivo(A) An evident weakness of the laminin network and a slight, but distinct expression of IFNγ were observed in SK-MES tumors harvested from hrIL-27 treated mice in comparison with control tumors. (X400). (B) In comparison with Calu-6 tumors from control mice, those from hrIL-27-treated mice presented a reduced percentage of cancer cells endowed with a distinct to strong expression of SHH. (X630). (C) In comparison with SK-MES tumors from control mice, those from hrIL-27-treated mice showed a reduced percentage of cancer cells endowed with a distinct to strong expression of OCT4A, SOX2, SOX9, NOTCH1, and KLF4. (OCT4A and SOX9: X400; SOX2, NOTCH1, and KLF4: X630). (D) Expression of Nestin was faint following hrIL-27 treatment, while it was distinct to strong in control tumors. Nuclear expression of SNAI1, SNAI2, and ZEB1 was less frequent in tumors from hrIL-27 treated mice than in control tumors, and the tumor cell surface expression of E-Cadherin was stronger in the former than in the latter. (Nestin: X630; SNAI1, SNAI2, ZEB1, and E-Cadherin: X400).
Mentions: Lastly immunohistochemical analyses revealed that the microvascular network of Calu-6 tumors from hrIL-27-treated mice was similar to that of the controls whereas that of SK-MES tumors from hrIL-27-treated mice was clearly impaired (Figure 2C and 2D) (Table 3) in association with a weakened laminin network and a faint, but distinct cancer cell expression of IFNγ (Figure 3A).

Bottom Line: In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression.Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects.In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Oncology, Istituto "Giannina Gaslini", Genova 16147, Italy.

ABSTRACT
Current therapies for Non-Small Cell Lung Cancer (NSCLC) still fail to significantly increase its survival rate. Here we asked whether Interleukin(IL)-27, which has revealed powerful antitumor activity and is toxicity-free in humans, is a promising therapeutic choice for NSCLC patients. IL-27's effects were tested on Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) cell lines and xenograft models. IL-27Receptor(R) expression was assessed in lung tissues from 78 NSCLC patients. In vitro, IL-27 was ineffective on cancer cell proliferation or apoptosis, but fostered CXCL3/GROγ/MIP2β expression. In vitro and in vivo, IL-27 down-regulated stemness-related genes, namely SONIC HEDGEHOG in AC cells, and OCT4A, SOX2, NOTCH1, KLF4 along with Nestin, SNAI1/SNAIL, SNAI2/SLUG and ZEB1, in SCC cells. In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression. Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects. In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease. Our data suggest that even immunocompromised or advancer NSCLC patients may benefit from IL-27's antitumor properties based on its ability to drive myeloid cells towards antitumor activities, and down-regulate stemness- and EMT-related genes in cancer cells.

Show MeSH
Related in: MedlinePlus