Limits...
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

Proliferation and apoptosis in PDXs treated with vehicle or p38 MAPK inhibitorProliferation and apoptosis levels were determined at early time points (day 5 for CCR-010 and CCR-024 and day 8 for CCR-038) and at the end of the experiment (day 10 for CCR-010 and CCR-024 and day 16 for CCR-038) by counting either Ki67+ and BrdU+ cells or Cleaved caspase-3+ cells. Proliferation and apoptosis in the initial tumors were given the value of 1 and relative indexes were determined for vehicle or PH797804-treated PDXs. At least eight fields were analyzed per tumor. Data represent means ± SEM (n ≥ 4). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496165&req=5

Figure 4: Proliferation and apoptosis in PDXs treated with vehicle or p38 MAPK inhibitorProliferation and apoptosis levels were determined at early time points (day 5 for CCR-010 and CCR-024 and day 8 for CCR-038) and at the end of the experiment (day 10 for CCR-010 and CCR-024 and day 16 for CCR-038) by counting either Ki67+ and BrdU+ cells or Cleaved caspase-3+ cells. Proliferation and apoptosis in the initial tumors were given the value of 1 and relative indexes were determined for vehicle or PH797804-treated PDXs. At least eight fields were analyzed per tumor. Data represent means ± SEM (n ≥ 4). *, p < 0.05; **, p < 0.01; ***, p < 0.001.

Mentions: Interfering with p38 MAPK signaling in AOM/DSS-induced colon tumors reduces proliferation and enhances death of the tumor cells [20]. Since p38 MAPK inhibition does not affect the differentiation status of the three PDXs tested, we determined cell proliferation and cell death indexes. We analyzed an early time point in the middle of the treatment (day 5 for CCR-010 and CCR-024; day 8 for CCR-038) and a late one at the end (day 10 for CCR-010 and CCR-024; day 16 for CCR-038). We found that for CCR-010 and CCR-024 tumors, cell proliferation measured by counting Ki67+ or BrdU+ cells was significantly reduced and apoptosis was increased in the mice treated with PH797804 (Figure 4). As expected from the tumor growth curves, the effect of p38 MAPK inhibition in both models was more important at the early times. In fact, impaired growth of CCR-010 and CCR-024 tumors was already observed as early as 2 days after starting the treatment with PH797804 (Figure 2). At late time points, tumors still showed decreased proliferation but apoptosis was not affected (Figure 4), which probably contributed to the PH797804-treated tumors starting to grow again slowly (Figure 2). In contrast, p38 MAPK inhibition reduced cell proliferation at the early time point without affecting apoptosis in CCR-038 tumors (Figure 4). In conclusion, p38 MAPK signaling can regulate the proliferation and survival of colon tumor cells in a tumor-type dependent manner but pharmacological inhibition of this pathway leads to reduced tumor growth in the three PDXs analyzed.


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)

Proliferation and apoptosis in PDXs treated with vehicle or p38 MAPK inhibitorProliferation and apoptosis levels were determined at early time points (day 5 for CCR-010 and CCR-024 and day 8 for CCR-038) and at the end of the experiment (day 10 for CCR-010 and CCR-024 and day 16 for CCR-038) by counting either Ki67+ and BrdU+ cells or Cleaved caspase-3+ cells. Proliferation and apoptosis in the initial tumors were given the value of 1 and relative indexes were determined for vehicle or PH797804-treated PDXs. At least eight fields were analyzed per tumor. Data represent means ± SEM (n ≥ 4). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Proliferation and apoptosis in PDXs treated with vehicle or p38 MAPK inhibitorProliferation and apoptosis levels were determined at early time points (day 5 for CCR-010 and CCR-024 and day 8 for CCR-038) and at the end of the experiment (day 10 for CCR-010 and CCR-024 and day 16 for CCR-038) by counting either Ki67+ and BrdU+ cells or Cleaved caspase-3+ cells. Proliferation and apoptosis in the initial tumors were given the value of 1 and relative indexes were determined for vehicle or PH797804-treated PDXs. At least eight fields were analyzed per tumor. Data represent means ± SEM (n ≥ 4). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
Mentions: Interfering with p38 MAPK signaling in AOM/DSS-induced colon tumors reduces proliferation and enhances death of the tumor cells [20]. Since p38 MAPK inhibition does not affect the differentiation status of the three PDXs tested, we determined cell proliferation and cell death indexes. We analyzed an early time point in the middle of the treatment (day 5 for CCR-010 and CCR-024; day 8 for CCR-038) and a late one at the end (day 10 for CCR-010 and CCR-024; day 16 for CCR-038). We found that for CCR-010 and CCR-024 tumors, cell proliferation measured by counting Ki67+ or BrdU+ cells was significantly reduced and apoptosis was increased in the mice treated with PH797804 (Figure 4). As expected from the tumor growth curves, the effect of p38 MAPK inhibition in both models was more important at the early times. In fact, impaired growth of CCR-010 and CCR-024 tumors was already observed as early as 2 days after starting the treatment with PH797804 (Figure 2). At late time points, tumors still showed decreased proliferation but apoptosis was not affected (Figure 4), which probably contributed to the PH797804-treated tumors starting to grow again slowly (Figure 2). In contrast, p38 MAPK inhibition reduced cell proliferation at the early time point without affecting apoptosis in CCR-038 tumors (Figure 4). In conclusion, p38 MAPK signaling can regulate the proliferation and survival of colon tumor cells in a tumor-type dependent manner but pharmacological inhibition of this pathway leads to reduced tumor growth in the three PDXs analyzed.

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