Biomarkers and signal transduction in lymphoma and prostate cancer
||Anette Gjörloff Wingren
||Anette Gjörloff Wingren
||Jenny L Persson, Pirkko Härkönen, Lunds universitet
||Medicinska fakulteten, Lund, UMAS cancerstiftelse, Malmö högskola, Kungliga fysiografiska Sällskapet
||2010-01-01 -- 2015-12-31
||Biofilms Research Center for Biointerfaces
||Faculty of Health and Society, The Department of Biomedical Science
Loss of protein tyrosine phosphatases (PTPs) has been reported in numerous experimental and clinical cancers. At least 30 different PTPs have been reported to be affected and loss can occur by genetic or epigenetic mechanisms. Several cell surface receptor tyrosine kinase (RTK) pathways are critical in tumorigenesis, by directing signalling cascades controlling proliferation and thereby survival. In Sweden alone, 2000 persons are diagnosed with malignant lymphoma yearly. The majority of malignant lymphomas are of B cell origin. Low-grade non-Hodgkin lymphoma (NHL) are indolent lymphomas that may initially involve a period of observation, without any treatment. The most common ones include follicular lymphoma (FL), mantle cell lymphoma (MCL) and B-cell chronic lymphatic leukemia (B-CLL). High-grade NHL are aggressive lymphomas with a high rate of proliferation. Diffuse large B cell lymphoma (DLBCL) show a high proliferation rate, are clinically aggressive and is the most frequent lymphoma subtype. In lymphoma, we are studying the PTPs SHP1, SHP2, HePTP, PTEN, LMW-PTP (ACP-1), the PTK ZAP70 and the molecules interacting with them.
The growth of prostatic epithelial cells is regulated in several ways, including steroid hormones and growth factors. The PTP SHP1 and SHP-2 are thought to modulate and inhibit them. Loss of SHP1 results in constitutive phosphorylation and activity of growth factor signalling. Our results show that the expression level of SHP1 is decreased in hormone-insensitive PC-3 and DU145 prostate cancer cells. The level of SPH1 protein in human prostate cancer samples in inversely correlated with progression of the disease. This suggests that SHP1 could have a tumor suppressor-like function in human prostate cancer. SHP-2 is structurally related to SHP-1, but with different function. SHP-2 has been reported to positively regulate the signalling pathways initiated by insulin, EGF, PDGF, and FGF, whereas it has been demonstrated that SHP-2 negatively regulates gp130 signalling triggered by IL-6. Both SHP-1 and SHP-2 are important regulators by dephosphorylating receptors of growth factors, cytokines and tyrosine-phosphorylated proteins associated with these receptors, but their expression and role in signalling pathways in prostate cancer are so far poorly investigated.
A better understanding of the molecular pathogenesis of cancer may eventually permit the development of therapeutic strategies that target tumor-specific molecular lesions. One novel way to treat cancer could be with cholesterol-lowering drugs, such as statins. One of our projects aim to understand how lymphoma cells are inhibited by statins.
Beskrivning på svenska
Tyrosin fosforylering är en mycket viktig mekanism i signal transduktion i eukaryota celler. Genom att använda cellinjer samt vävnad från patienter med cancer, studerar vi reglering och funktion av signal transduktionsmolekyler. Många patienter med lymfom erhåller samma sorts terapi, trots att sjukdomen är heterogen. Prostata och bröstcancer tillhör nu de vanligaste formerna av cancer. Bättre prognostisk kunskap behövs för att finna bra terapimetoder. Våra studier avser att finna tyrosin fosfataser som utgör nyckelmolekyler i utveckling, reglering och upprätthållande av en cancercell. Vi studerar tyrosin fosfataserna SHP1, SHP2, HePTP, PTEN, LMW-PTP (ACP-1), och tyrosin kinaset ZAP70 samt de molekyler som interagerar med dem.
Dessa molekyler har potential att bli användbara som diagnostiska och prognostiska markörer i cancer.