Relevance of AKT Pathway Protein Expression in Gastrointestinal Kaposi Sarcoma
Alina Badescu, Anne Couvelard, Adriana Handra-Luca. APHP U Paris13, Bobigny, France, Metropolitan; APHP U Paris7, Paris, France, Metropolitan
Background: Gastrointestinal location of Kaposi sarcoma (KS) is classical but rare. Activation of the AKT pathway signaling pathway by KSHV/HHV8 encoded proteins plays a central role in Kaposi sarcomagenesis. There is increasing evidence that rapamycin, interfering with AKT pathway proteins, may be useful in the treatment of KS, including in HIV positive patients.
Design: The expression of AKT pathway proteins (AKT, 4EBP1, PTEN, mTOR) was assessed on tumor biopsies of 19 gastrointestinal KS (17 patients) by immunohistochemistry using antibodies directed against their activated forms. The percentage of positive cells was assessed in tumor and non-tumor tissues. The median was used as cutoff for classifying low/high expression. Protein expression was analysed with regard to patients' and tumor characteristics.
Results: Patients' age varied between 28-75 years (median 37), the gender ratio was women:men of 6:11 and, 16/17 patients were HIV positive. Twelve (12) tumors were gastric and 7 intestinal (duodenum and colorectum, 2 and 5 respectively). The tumor vascular component varied between 25-80% of tumor mass (median 45%), and comprised classical vessels as well as tumor slits (vascular spaces lined directly by tumor cells). Tumor hemoragia and hemosiderin were observed in 5 and 7 KS.
Tumor cell nuclear expression of AKT, 4EBP1, PTEN, and mTOR was observed in 42%, 88%, 65% and 100% KS and, vascular expression in 42%, 76 %, 53% and 94% KS. Nuclear AKT and 4EBP1 tumor and vascular expressions were coordinated (p<0.01 and 0.04). AKT was overexpressed in intratumor vessels as compared to extratumor normal vessels (p=0.04).
Tumor nuclear AKT and 4EBP1 were related to lack of hemoragia (0.04 and 0.07 respectively) whereas vascular AKT expression related to presence of a low vascular component (p=0.05). Expression of tumor nuclear 4EBP1 at high level related to a high slit component (p=0.04). Tumor nuclear PTEN correlated to a high vascular component and to presence of intratumor hemosiderin pigment (0.04 for both comparisons) while when expressed at high levels to hemorragia.
Conclusions: The results of our study suggest that activated forms of AKT pathway proteins are frequently expressed in gastrointestinal Kaposi sarcomas, explaining the response to drugs targeting this pathway, such as rapamicin. Interestingly, AKT pathway proteins have variate impacts on tumor angiogenesis and vascular permeability, AKT being associated with anti-angiogenic features whereas PTEN and 4EBP1 with pro-angiogenic tumor features.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 69, Wednesday Morning