Transforming growth factor-β, MAPK and Wnt signaling interactions in colorectal cancer

Cheruku, Harish R.; Mohamedali, Abidali; Cantor, David; Tan, Sock Hwee; Nice, Edouard C.; Baker, Mark S.

doi:10.1016/j.euprot.2015.06.004

Cited by 38 publications

(30 citation statements)

References 163 publications

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“…The activation of ERK1/2 signaling is very common in colon cancer and is vital for the growth of CRC cells (Cheruku et al, 2015;Setia et al, 2014), We previously observed that PTHrP stimulates cell proliferation and cell cycle progression through ERK MAPK in tumor intestinal cells (Martín et al, 2014;Calvo et al, 2014). Moreover, our recent studies revealed that PTHrP can promote cell migration through RSK/ERK MAPK in Caco-2 cells and HCT116 cells (Calvo et al, 2017).…”

Section: Pthrp Induces the Phosphorylation And Activation Of Src Kinamentioning

confidence: 98%

“…It is known that several mitogenic signaling pathways play key roles in maintaining the growth and proliferation of CRC. Activation of ERK1/2 MAPK signaling is very common in CRC (Cheruku et al, 2015); it has been reported that MEK/ERK signaling contributes to 5-FU resistance and supports CRC cell growth (Yang et al, 2016a) whereas small molecular inhibitors targeting ERK signaling have shown anti-tumor effects on the colon cancer (Peng et al, 2013). Like MAPKs, there is increasing evidence that the activation of PI3K/Akt pathway is associated with CRC, and can convert differentiated human gastric or colonic mucosa to a less differentiated and more malignant phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP

Martín

Gigola

Zwenger

et al. 2018

Molecular and Cellular Endocrinology

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Although PTHrP is implicated in several cancers, its role in chemoresistance is not fully elucidated. We found that in CRC cells, PTHrP exerts proliferative and protective effects and induces cell migration. The aim of this work was to further study the effects of PTHrP in CRC cells. Herein we evidenced, for the first time, that PTHrP induces resistance to CPT-11 in Caco-2 and HCT116 cells; although both cell lines responded to the drug through different molecular mechanisms, the chemoresistance by PTHrP in these models is mediated through ERK, which in turn is activated by PCK, Src and Akt. Moreover, continue administration of PTHrP in nude mice xenografts increased the protein levels of this MAPK and of other markers related to tumorigenic events. The understanding of the molecular mechanisms leading to ERK 1/2 activation and the study of ERK targets may facilitate the development of new therapeutic strategies for CRC treatment.

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Section: Pthrp Induces the Phosphorylation And Activation Of Src Kinamentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP

Martín

Gigola

Zwenger

et al. 2018

Molecular and Cellular Endocrinology

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“…The MAPK cascades are membrane to nucleus signaling modules that respond to oxidative stress which lead to phosphorylation and activation of down-stream genes required for CRC 87 , 88 . For example, the EGFR cys797 can be oxidized and activated by ROS, which initiates the MAPK cascade that is responsible for CRC 89 .…”

Section: The Relation Between Oxidative Stress and Crcmentioning

confidence: 99%

Redox Imbalance in the Development of Colorectal Cancer

et al. 2017

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Redox imbalance is resulted from the destruction of balance between oxidants and antioxidants. The dominant oxidants are reactive oxygen species (ROS), which are involved in multiple cellular processes by physiologically transporting signal as a second messenger or pathologically oxidizing DNA, lipids, and proteins. Generally speaking, low concentration of ROS is indispensable for cell survival and proliferation. However, high concentration of ROS is cytotoxic. Additionally, ROS are now known to induce the oxidative modification of macromolecules especially proteins. The redox modification of proteins is involved in numerous biological processes related to diseases including CRC. Herein, we attempt to afford an overview that highlights the crosstalk between redox imbalance and CRC.

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“…Recent studies suggest TGF‐β signalling may lead to muscle atrophy by a mechanism which is ROS dependent and plays a central role in fibrosis . TGF‐β signals can activate SMAD‐dependent canonical pathway, as well as induce the JNK/p38 MAPK signalling pathway (non‐canonical) . However, the signalling pathway underlying TGF‐β effect upon ECM expression in the tumour of cachectic patients has not been previously identified.…”

Section: Discussionmentioning

confidence: 99%

“…60 TGF-β signals can activate SMADdependent canonical pathway, 61 as well as induce the JNK/p38 MAPK signalling pathway (non-canonical). 62 However, the signalling pathway underlying TGF-β effect upon ECM expression in the tumour of cachectic patients has not been previously identified. We also found that all isoforms of TGF-β were increased (as compared with WSC) in the tumour samples obtained from the cachectic patients.…”

Section: Discussionmentioning

confidence: 99%

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

Lima

Simoes

Castro

et al. 2019

J cachexia sarcopenia muscle

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Background Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro‐environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro‐environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients. Methods 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components. Results Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte–macrophage colony‐stimulating factor, interferon‐α, and interleukin (IL)‐8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight‐stable counterparts. Also, IL‐8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α‐smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)‐β1, TGF‐β2, and TGF‐β3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen‐activated protein kinase alteration. Hypoxia‐inducible factor‐1α mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight‐stable group (P = 0.005). Conclusions Our results demonstrate TGF‐β pathway activation in the tumour in cachexia, through the (non‐canonical) mitogen‐activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF‐β‐induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.

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Transforming growth factor-β, MAPK and Wnt signaling interactions in colorectal cancer

Cited by 38 publications

References 163 publications

Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP

Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP

Redox Imbalance in the Development of Colorectal Cancer

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

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