Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation

Abstract

Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis (LAM), a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogeneic growth factor VEGF-D are elevated significantly in LAM. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in LAM. Here we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from LAM patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent anti-proliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of LAM. In TSC2-deficient cells, Syk signaling increased expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated production of VEGF-D. In clinical isolates of PBMC from LAM patients, VEGF-D expression was elevated. Further, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for LAM growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation.

Possible Novel Therapeutic Targets in Lymphangioleiomyomatosis Treatment

“…As expected, deregulated expression and activation of Syk was detected in TSC2-deficient cells and LAM lung lesions (56). Furthermore, Syk inhibitor fostamatinib reduced the proliferation of TSC2-deficient cells in vitro and suppressed TSC2-null xenograft tumor development in vivo (56). This study identified a Syk-dependent signaling inducing VEGF-D expression in peripheral blood mononuclear cells by monocyte chemoattractant protein (MCP)-1, which was elevated via signal transducer and activator of transcription (Stat3) signaling downstream of the mTORC1 signaling (56), demonstrating the strong therapeutic potential of Syk in LAM treatment.…”

“…Hence, the hypothesis that Syk may be involved in LAM pathogenesis is worthy to be taken into consideration. As expected, deregulated expression and activation of Syk was detected in TSC2-deficient cells and LAM lung lesions (56). Furthermore, Syk inhibitor fostamatinib reduced the proliferation of TSC2-deficient cells in vitro and suppressed TSC2-null xenograft tumor development in vivo (56).…”

“…Furthermore, Syk inhibitor fostamatinib reduced the proliferation of TSC2-deficient cells in vitro and suppressed TSC2-null xenograft tumor development in vivo ( 56 ). This study identified a Syk-dependent signaling inducing VEGF-D expression in peripheral blood mononuclear cells by monocyte chemoattractant protein (MCP)-1, which was elevated via signal transducer and activator of transcription (Stat3) signaling downstream of the mTORC1 signaling ( 56 ), demonstrating the strong therapeutic potential of Syk in LAM treatment. Fostamatinib, as a Syk inhibitor, has been approved by the FDA to treat immune thrombocytopenia, but clinical trials studying its efficacy and safety in LAM treatment still wait to be accomplished.…”

Lymphangioleiomyomatosis: a case report and review of diagnosis and treatment

“… 35 Another study demonstrated that Syk inhibition is a potential therapy for patients with LAM. 36 Recent research involving cells derived from patients with LAM showed that estrogen increased cell resistance to anoikis in vitro that was accompanied by a decreased accumulation of the proapoptotic protein, Bim, an activator of anoikis. Therefore, targeting Bim may be a plausible future treatment strategy for patients with LAM.…”

Circulating Biomarkers From the Phase 1 Trial of Sirolimus and Autophagy Inhibition for Patients With Lymphangioleiomyomatosis

“…The study of peripheral blood in patients with LAM has previously identified multiple molecules 6 that are differentially present in the sera of women with LAM. The most important of these is vascular endothelial growth factor (VEGF)-D, a diagnostic biomarker of LAM in clinical use [7][8][9] and a candidate biomarker of therapeutic response to rapamycin. 10 To date, however, no large-scale studies of sera from women with LAM have been reported.…”