Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer

Abstract

The expression of fatty acid synthase (FAS), a key lipogenic enzyme and potential target for antineoplastic therapy, was analyzed in 87 frozen needle biopsies of prostate cancer using a highly sensitive immunohistochemical detection technique (Envision). In comparison to normal or benign, hyperplastic glandular structures, which were all negative for FAS staining, immunohistochemical signal was evident in 24/25 low grade prostatic epithelial neoplasia (PIN) lesions, in 26/26 high grade PIN lesions and in 82/87 invasive carcinomas. Staining intensity tended to increase from low grade to high grade PIN to invasive carcinoma. Cancers with a high FAS expression had an overall high proliferative index. No correlation was found between FAS expression and lipid accumulation. These findings indicate that increased FAS expression is one of the earliest and most common events in the development of prostate cancer, suggesting that FAS may be used as a general prostate cancer marker and that antineoplastic therapy based on FAS inhibition may be an option for chemoprevention or curative treatment for nearly all prostate cancers. © 2002 Wiley-Liss, Inc. Key words: fatty acid synthase; lipogenesis; cancer development; tumor marker Development and progression of cancer is commonly viewed as a multistep process reflecting genetic alterations that drive the progressive transformation of normal cells into highly malignant ones. In the case of prostate cancer, which characteristically develops as a multifocal and heterogeneous lesion, it has been difficult to find common alterations that mark discrete steps in its development. One of the molecular changes reported in various cancers, is overexpression of Oncogenic Antigen-519 (OA-519), 1 OA-519 is the marker designation for a protein sharing epitopes with a haptoglobin-related protein (hrp), found to be overexpressed in breast cancers with a higher risk for tumor recurrence. 1 Subsequent characterization of this protein revealed that it corresponds to fatty acid synthase (FAS), a key metabolic enzyme that plays a central role in the de novo biosynthesis of fatty acids. 2 The preferential expression of FAS in cancer cells has sparked studies to exploit FAS as a potential target for antineoplastic therapy. According to these studies, inhibition of FAS activity induces cell death in FAS-overexpressing cancer cell lines and prolongs survival of xenograft hosts. [3][4][5] In most reports on OA519/FAS overexpression published thus far, increased FAS expression was found only in a subset of cancers, 6 -12 questioning its role in the overall cancer process and limiting the applicability of anti-FAS therapy. In the first study of OA-519 expression in prostate cancer for instance, Shurbaji et al. 6 examined 42 paraffin-embedded prostate adenocarcinoma samples with an anti-OA-519/hrp antibody and found positive staining in 48% of the cancer samples. Little or no staining was observed in normal or hyperplastic prostate tissue. In a second study by this same group, 7 using an antibo...

Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays

“…Fatty acid synthase mRNA and protein upregulation is one of the earliest and most common events in the development of prostate carcinoma, and a strong association between FASN and tumour initiation has been shown (Swinnen et al, 2002;Rossi et al, 2003). Accordingly, we found FASN expression to be much stronger in tumours than in BPH.…”

“…Fatty acid synthase immunostaining was homogeneously dispersed throughout the cytoplasm as described before (Swinnen et al, 2002;Rossi et al, 2003). Subcellular staining of MYC was predominantly cytoplasmic: in BPH, perinuclear focal granular immunostaining was observed on the luminal site of the cells, whereas malignant secretory cells showed a diffuse cytoplasmic immunostaining.…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Although enzymes of mitochondrial β-oxidation are not increased in prostate cancer [140], it has been shown that etomoxir-mediated inhibition of mitochondrial β-oxidation at the level of carnitine palmitoyltransferase 1 induces cell death in prostate cancer cell lines [143]. Interestingly, prostate cancer also induces fatty acid biosynthesis by overexpressing fatty acid synthase early during tumor progression without lipid accumulation [144,145], which is further consistent with 11 C-acetate PET/CT experiments [146]. Why a futile cycle of simultaneous fatty acid oxidation and fatty acid synthesis is beneficial to prostate cancer cells remains an open question.…”

Fatty acid synthase: a novel target for antiglioma therapy

“…Thus, FAS expression is generally low to undetectable in normal human tissues, other than the liver and adipose tissue. In contrast, FAS is overexpressed in many human tumours, including carcinoma of the breast (Milgraum et al, 1997;Wang et al, 2001b), prostate (Epstein et al, 1995;Swinnen et al, 2002), colon (Rashid et al, 1997), ovary (Gansler et al, 1997), endometrium (Pizer et al, 1998b), mesothelium (Gabrielson et al, 2001), lung (Piyathilake et al, 2000), thyroid (Vlad et al, 1999), and stomach (Kusakabe et al, 2002). Abnormally active endogenous fatty acid metabolism appears to be important for cancer cell proliferation and survival (Ookhtens et al, 1984).…”

“…Abnormally active endogenous fatty acid metabolism appears to be important for cancer cell proliferation and survival (Ookhtens et al, 1984). Moreover, overexpression of FAS in breast, prostate, and thyroid cancers has been associated with more aggressive malignancies (Epstein et al, 1995;Gansler et al, 1997;Vlad et al, 1999;Swinnen et al, 2002). The preferential expression of FAS in cancer cells suggests that FAS could be a promising target for antitumour therapy (Kuhajda, 2006).…”