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Mechanisms of sphingosine 1-phosphate receptor signalling in cancer

Patmanathan SN, Wang W, Yap LF, Herr DR, Paterson IC

Cell Signal, 2017 06;34:66-75.
PMID: 28302566 DOI: 10.1016/j.cellsig.2017.03.002

S1P is a small bioactive lipid which exerts its effects following binding to a family of five G protein-coupled receptors, known as S1P1-5. Following receptor activation, multiple signalling cascades are activated, allowing S1P to regulate a range of cellular processes, such as proliferation, apoptosis, migration and angiogenesis. There is strong evidence implicating the involvement of S1P receptors (S1PRs) in cancer progression and the oncogenic effects of S1P can result from alterations in the expression of one or more of the S1PRs and/or the enzymes that regulate the levels of S1P. However, cooperativity between the individual S1PRs, functional interactions with receptor tyrosine kinases and the sub-cellular localisation of the S1PRs within tumour cells also appear to play a role in mediating the effects of S1PR signalling during carcinogenesis. Here we review what is known regarding the role of individual S1PRs in cancer and discuss the recent evidence to suggest cross-talk between the S1PRs and other cellular signalling pathways in cancer. We will also discuss the therapeutic potential of targeting the S1PRs and their downstream signalling pathways for the treatment of cancer.

Matched MeSH terms: Receptor Protein-Tyrosine Kinases/metabolism
Fulltext Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells

Abbaspour Babaei M, Kamalidehghan B, Saleem M, Huri HZ, Ahmadipour F

Drug Des Devel Ther, 2016;10:2443-59.
PMID: 27536065 DOI: 10.2147/DDDT.S89114

c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence.

Matched MeSH terms: Receptor Protein-Tyrosine Kinases/metabolism*
Expression of DDR1 and DVL1 in invasive ductal and lobular breast carcinoma does not correlate with histological type, grade and hormone receptor status

Ameli F, Rose IM, Masir N

Asian Pac J Cancer Prev, 2015;16(6):2385-90.
PMID: 25824769

BACKGROUND: Invasive ductal (IDC) and lobular (ILC) carcinomas are the common histological types of breast carcinoma which are difficult to distinguish when poorly differentiated. Discoidin domain receptor (DDR1) and Drosophila dishevelled protein (DVL1) were recently suggested to differentiate IDC from ILC.
OBJECTIVES: To assess the expression of DDR1 and DVL1 and their association with histological type, grading and hormonal status of IDC and ILC.
MATERIALS AND METHODS: This cross sectional study was conducted on IDC and ILC breast tumours. Tumours were immunohistochemically stained for (DDR1) and (DVL1) as well as estrogen receptor (ER), progesterone receptor (PR) and C-erbB2 receptor. Demographic data including age and ethnicity were obtained from patient records.
RESULTS: A total of 51 cases (30 IDCs and 21 ILCs) were assessed. DDR1 and DVL1 expression was not significantly associated with histological type (p=0.57 and p=0.66 respectively). There was no association between DDR1 and DVL1 expression and tumour grade (p=0.32 and p=1.00 respectively), ER (p=0.62 and 0.50 respectively), PR (p=0.38 and p=0.63 respectively) and C-erbB2 expression (p=0.19 and p=0.33 respectively) in IDC. There was no association between DDR1 and DVL1 expression and tumour grade (p=0.52 and p=0.33 respectively), ER (p=0.06 and p=0.76 respectively), PR (p=0.61 and p=0.43 respectively) and C-erbB2 expression (p=0.58 and p=0.76 respectively) in ILC.
CONCLUSIONS: This study revealed that DDR1 and DVL1 are present in both IDC and ILC regardless of the tumour differentiation. More studies are needed to assess the potential of these two proteins in distinguishing IDC from ILC in breast tumours.

Matched MeSH terms: Receptor Protein-Tyrosine Kinases/metabolism*
Immunohistochemical localisation of RET and p53 mutant protein of thyroid lesions in a North-Eastern Malaysian population and its prognostic implications

Omar E, Madhavan M, Othman NH

Pathology, 2004 Apr;36(2):152-9.
PMID: 15203751

To investigate RET and p53 expression in local thyroid lesions, in order to shed light on the pathogenesis of papillary carcinoma and explain the high prevalence of this condition among the nodular hyperplasia (multi-nodular goitre) cases.

Matched MeSH terms: Receptor Protein-Tyrosine Kinases/metabolism*