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Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors.

Gupta J, Igea A, Papaioannou M, Lopez-Casas PP, Llonch E, Hidalgo M, Gorgoulis VG, Nebreda AR - Oncotarget (2015)

Bottom Line: We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival.The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis.Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.

ABSTRACT
Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.

No MeSH data available.


Related in: MedlinePlus

Tumor histology in PDXs treated with vehicle or p38 MAPK inhibitorRepresentative H&E stained sections of PDXs treated with vehicle or PH797804. Initial tumors refers to the beginning of the treatment, Vehicle early and p38 inhibitor early refer to day 5 of treatment in the case of CCR-010 and CCR-024 and day 8 in the case of CCR-038. Vehicle late and p38 inhibitor late refer to the end of the treatment, day 10 for CCR-10 and CCR-024 and day 16 for CCR-038. Treatment with the p38 MAPK inhibitor did not affect the architecture of tumors compared to vehicle treatment. Scale bars, 100 μm.
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Figure 3: Tumor histology in PDXs treated with vehicle or p38 MAPK inhibitorRepresentative H&E stained sections of PDXs treated with vehicle or PH797804. Initial tumors refers to the beginning of the treatment, Vehicle early and p38 inhibitor early refer to day 5 of treatment in the case of CCR-010 and CCR-024 and day 8 in the case of CCR-038. Vehicle late and p38 inhibitor late refer to the end of the treatment, day 10 for CCR-10 and CCR-024 and day 16 for CCR-038. Treatment with the p38 MAPK inhibitor did not affect the architecture of tumors compared to vehicle treatment. Scale bars, 100 μm.

Mentions: To investigate in more detail the reduction in tumor growth observed upon p38 MAPK inhibition, we examined possible alterations in tumor histology. H&E-stained sections from the initial tumors and from PDXs of mice treated with vehicle or the p38 MAPK inhibitor were analyzed at different time points but no differences were found (Figure 3). We also analyzed the presence of mucus secreting epithelial cells by PAS staining as well as the neuroendocrine differentiation by CD56 immunostaining. However, pharmacological inhibition of p38 MAPK affected neither the neuroendocrine differentiation in model CCR-010 nor the mucus secreting epithelial cells in model CCR-038 (Suppl. Figure S1). These results indicate that the reduced tumor growth observed upon p38 MAPK inhibition does not correlate with changes in the differentiation stage of the tumoral cells.


Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors.

Gupta J, Igea A, Papaioannou M, Lopez-Casas PP, Llonch E, Hidalgo M, Gorgoulis VG, Nebreda AR - Oncotarget (2015)

Tumor histology in PDXs treated with vehicle or p38 MAPK inhibitorRepresentative H&E stained sections of PDXs treated with vehicle or PH797804. Initial tumors refers to the beginning of the treatment, Vehicle early and p38 inhibitor early refer to day 5 of treatment in the case of CCR-010 and CCR-024 and day 8 in the case of CCR-038. Vehicle late and p38 inhibitor late refer to the end of the treatment, day 10 for CCR-10 and CCR-024 and day 16 for CCR-038. Treatment with the p38 MAPK inhibitor did not affect the architecture of tumors compared to vehicle treatment. Scale bars, 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496165&req=5

Figure 3: Tumor histology in PDXs treated with vehicle or p38 MAPK inhibitorRepresentative H&E stained sections of PDXs treated with vehicle or PH797804. Initial tumors refers to the beginning of the treatment, Vehicle early and p38 inhibitor early refer to day 5 of treatment in the case of CCR-010 and CCR-024 and day 8 in the case of CCR-038. Vehicle late and p38 inhibitor late refer to the end of the treatment, day 10 for CCR-10 and CCR-024 and day 16 for CCR-038. Treatment with the p38 MAPK inhibitor did not affect the architecture of tumors compared to vehicle treatment. Scale bars, 100 μm.
Mentions: To investigate in more detail the reduction in tumor growth observed upon p38 MAPK inhibition, we examined possible alterations in tumor histology. H&E-stained sections from the initial tumors and from PDXs of mice treated with vehicle or the p38 MAPK inhibitor were analyzed at different time points but no differences were found (Figure 3). We also analyzed the presence of mucus secreting epithelial cells by PAS staining as well as the neuroendocrine differentiation by CD56 immunostaining. However, pharmacological inhibition of p38 MAPK affected neither the neuroendocrine differentiation in model CCR-010 nor the mucus secreting epithelial cells in model CCR-038 (Suppl. Figure S1). These results indicate that the reduced tumor growth observed upon p38 MAPK inhibition does not correlate with changes in the differentiation stage of the tumoral cells.

Bottom Line: We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival.The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis.Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.

ABSTRACT
Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.

No MeSH data available.


Related in: MedlinePlus