Expression of Activated Akt and PTEN in Malignant Melanomas : Relationship With Clinical Outcome

Slipicevic, Ana; Holm, Ruth; Nguyen, Minh‐Thanh; Bøhler, Per J.; Davidson, Ben; Flørenes, Viví Ann

doi:10.1309/yt58-wwmt-a6yr-1prv

Cited by 44 publications

(52 citation statements)

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“…The role of PTEN as a negative regulator of AKT is well documented in both cell line models and tumour samples (Stambolic et al, 1998;Sun et al, 1999;Kurose et al, 2001;Choe et al, 2003). However, others have also identified a positive correlation between expressions of the two proteins by immunostaining (Panigrahi et al, 2004;Slipicevic et al, 2005;Wang et al, 2005). This might mean that in tumours, the regulatory relationship between AKT and PTEN is not linear.…”

Section: Discussionmentioning

confidence: 99%

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

et al. 2008

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Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT -PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P ¼ 0.006), non-serous tumour type (P ¼ 0.042) and in multivariate analysis with a longer progression-free survival (P ¼ 0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P ¼ 0.011). Positive pAKT staining was associated with advanced-stage disease (P ¼ 0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis.

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Section: Discussionmentioning

confidence: 99%

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

et al. 2008

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“…PTEN regulates PIP 3 levels, and its inactivation results in accumulation of PIP 3 , AKT hyperphosphorylation, and enhanced cell survival/ proliferation. In melanoma, allelic loss or altered expression of PTEN comprises 20% and 40% of melanoma tumors, respectively (Pollock et al 2002;Mikhail et al 2005;Slipicevic et al 2005;Goel et al 2006), although somatic point mutations and homozygous deletions are rarely observed. Functionally, ectopic expression of PTEN in PTEN-deficient melanoma cells can abolish phospho-AKT activity, induce apoptosis, and suppress growth, tumorigenicity, and metastasis (Robertson et al 1998;Stewart et al 2002;Stahl et al 2003; for review, see Robertson 2005).…”

Section: Pten Negative Regulator Of Phosphatidylinositol 3-kinase (Pmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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“…Immunostains for cyclins A, D1 and D3, Ki-67, p21 WAF1/CIP1 , p27 kip1 , pERK1/2, pAkt and TrkA are described previously. [20][21][22][23][24][25][26] Five semiquantitative classes were used to describe the number of stained cells: negative, r5%, 6-25%, 26-75%, 76-100%. Both nuclear and cytoplasmic staining was scored.…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

“…Finally, the presence of p-p38 and p-JNK in the cytoplasm was positively correlated to each other (P ¼ 0.003) in superficial spreading melanomas. Expression levels of cyclins A, D3, p21 WAF1/CIP1 , p-ERK1/2, p-Akt and p-TrkA were scored as described in [20][21][22][23][24][25] . Expression levels of cyclin A and Ki-67, cyclin D3, p21WAF/CIP1, p-ERK1/2 and p-Akt were scored as described in Florenes et al, 21,25 Maelandsmo et al, 22 Jorgensen et al 23 and Slipicevic et al 24 Cell signaling in melanoma K Jørgensen et al…”

Section: Cell Signaling In Melanomamentioning

confidence: 99%

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

2006

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Signaling pathways regulating cell proliferation and survival have become attractive targets for anticancer strategies. In the present study, we analyzed by immunohistochemistry, a panel of benign nevi, superficial spreading and nodular primary melanomas and metastases for expression of activated p38/mitogen-activated protein kinase (p-p38) and c-jun N-terminal kinase (JNK) (p-JNK) and correlated the findings with known prognostic variables. Twenty-five and 35% of the primaries and 9 and 25% of the metastases expressed variable levels of p-p38 and p-JNK, respectively. In benign nevi, 73.5% expressed p-JNK and 7% expressed p-p38. For patients with superficial spreading melanomas, high level of cytoplasmic p-JNK was associated with thicker tumors (P ¼ 0.017) and shorter disease-free survival (P ¼ 0.003) as well as with markers of cell proliferation (cyclin A (P ¼ 0.017) and p21 (P ¼ 0.021)). In nodular melanomas, nuclear p-p38 was associated with Ki-67 (P ¼ 0.012), but neither cytoplasmic nor nuclear localized p-p38 was associated with disease outcome. Of note, in superficial spreading melanomas, a positive correlation between cytoplasmic p-JNK and cytoplasmic p-extracellular signal-regulated kinase ERK1/2 (P ¼ 0.005) and p-p38 (P ¼ 0.003) was observed. Likewise, p-p38 in cytoplasm was positively associated with cytoplasmic p-ERK1/2 (Po0.0005) and p-Akt (P ¼ 0.047). In contrast, except for a positive correlation between nuclear p-p38 and membranous p-TrkA (P ¼ 0.02), no correlation between the activation status of the different signaling pathways was observed in nodular melanomas. In conclusion, our results suggest that in benign nevi activated JNK may have a role in restricting uncontrolled cell proliferation or survival. However, during tumor progression, activation of JNK is associated with cell proliferation and shorter relapse-free period for patients with superficial spreading melanomas, suggesting that the JNK activation status could be a marker for clinical outcome in at least a subgroup of malignant melanoma. In contrast, activation of p38 seems to play a less important role in development and progression of malignant melanomas.

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Expression of Activated Akt and PTEN in Malignant Melanomas : Relationship With Clinical Outcome

Cited by 44 publications

References 0 publications

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

Malignant melanoma: genetics and therapeutics in the genomic era

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

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