Although it is generally accepted that FLCN has a role in mTOR signalling, precisely what this role is remains unclear (as illustrated in our signalling diagram and described here). mTOR signalling is known to control cell growth, proliferation and energy sensing and is dysregulated in a number of diseases, including cancer (reviewed by Laplante and Sabatini, 2012). Building on work by Furuya et al., 2012 (described in this blog post), Nishii et al demonstrate that components of the mTOR pathway are activated in BHD lung tissue and that there is increased vascularisation of subpleural lung cysts, which they attribute to increased HIF-1a and VEGF expression.
Nishii et al. report the case of a 33 year old female patient who presented in clinic with recurrent pneumothoraces. Computerised tomography (CT) and thoracoscopy revealed the presence of bilateral pulmonary lung cysts, predominantly localised in the subpleural region. This patient did not present with skin or kidney lesions but had a family history of pneumothorax. Genetic testing showed that the patient had a splicing mutation predicted to lead to the skipping of exon 6, which was confirmed by RT-PCR, and she was thus diagnosed with BHD.
Using Western blot and immunohistochemical staining on lung tissue resected from the patient, Nishii et al. demonstrated that the levels of phosphorylated mTOR and pS6 (targets of mTORC1) and AKT (a target of mTORC2) were increased in the cells lining cysts, compared to control lung tissue. These results suggest that FLCN inhibits mTOR signalling in normal lung tissue. Additionally, the authors noted that some lung cysts had increased vascularisation. This was attributed to the increased expression of HIF-1a and VEGF – both angiogenesis factors – that was seen in these cysts.
The pathogenesis of the lung cysts seen in BHD syndrome is not fully understood at present. These data lead the authors to suggest that dysregulated mTOR signalling due to FLCN haploinsufficiency causes cyst formation. HIF-1a is activated by mTOR signalling (Hudson et al., 2002) and in turn activates VEGF (Mazure et al., 1996); thus mTOR dysregulation may also lead to increased vascularisation of cysts, which may further facilitate cyst formation.
While much of the research investigating the role of FLCN in mTOR signalling has concentrated on its role in renal tumour development, this paper and related studies suggest that the dysregulation of mTOR signalling may also be responsible for lung cyst formation. Rapamycin (also known as Sirolimus) and Hypericin inhibit mTOR and HIF-1a respectively, and have been used in clinical trials to treat cancer, reportedly with some success (as discussed here and here). Therefore, they may be plausible candidates to treat the pulmonary symptoms of BHD.
Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, Hsu YH, Fujii T, Okada A, Kuroda N, Moritani S, Mizuno H, Nagashima Y, Nagahama K, Hiroshima K, Yoshino I, Nomura F, Aoki I, & Nakatani Y (2012). Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. The American journal of surgical pathology, 36 (4), 589-600 PMID: 22441547
Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, & Abraham RT (2002). Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Molecular and cellular biology, 22 (20), 7004-14 PMID: 12242281
Laplante M, & Sabatini DM (2012). mTOR signaling in growth control and disease. Cell, 149 (2), 274-93 PMID: 22500797
Mazure NM, Chen EY, Yeh P, Laderoute KR, & Giaccia AJ (1996). Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer research, 56 (15), 3436-40 PMID: 8758908
Nishii T, Tanabe M, Tanaka R, Matsuzawa T, Okudela K, Nozawa A, Nakatani Y, & Furuya M (2013). Unique mutation, accelerated mTOR signaling and angiogenesis in the pulmonary cysts of Birt-Hogg-Dubé syndrome. Pathology international, 63 (1), 45-55 PMID: 23356225