Intratumoral hypoxia is a well-known feature of solid cancers and constitutes a major contributor to cancer metastasis and poor outcomes including melanoma.,Leucine-rich repeats and Ig-like domains 1 (LRIG1) participate in the aggressive progression of several tumors, where its expression is frequently decreased.,In the present study, hypoxia exposure aggravated melanoma cell invasion, migration, vasculogenic mimicry (VM), and epithelial-mesenchymal transition (EMT).,During this process, LRIG1 expression was also decreased.,Importantly, overexpression of LRIG1 notably counteracted hypoxia-induced invasion, migration, and VM, which was further augmented after LRIG1 inhibition.,Mechanism analysis corroborated that LRIG1 elevation muted hypoxia-induced EMT by suppressing E-cadherin expression and increasing N-cadherin expression.,Conversely, cessation of LRIG1 further potentiated hypoxia-triggered EMT.,Additionally, hypoxia stimulation activated the epidermal growth factor receptor (EGFR)/ERK pathway, which was dampened by LRIG1 up-regulation but further activated by LRIG1 inhibition.,More important, blocking this pathway with its antagonist erlotinib abrogated LRIG1 suppression-induced EMT, and subsequently cell invasion, migration, and VM of melanoma cells under hypoxia.,Together, these findings suggest that LRIG1 overexpression can antagonize hypoxia-evoked aggressive metastatic phenotype by suppressing cell invasion, migration, and VM via regulating EGFR/ERK-mediated EMT process.,Therefore, these findings may provide a promising target for melanoma therapy.
Trials dedicated to metastatic uveal melanoma are needed because of the poor prognosis of this rare cancer and because its biology is distinct from that of cutaneous melanoma.Agents targeting the MEK/ERK/MAP kinase pathways are being tested.,Trials dedicated to metastatic uveal melanoma are needed because of the poor prognosis of this rare cancer and because its biology is distinct from that of cutaneous melanoma.,Agents targeting the MEK/ERK/MAP kinase pathways are being tested.,In experimental models, bevacizumab suppressed in vitro growth and in vivo hepatic metastasis of ocular melanoma cells.,Additional preclinical data suggested a potential benefit when combining bevacizumab with dacarbazine.,This noncomparative phase II study evaluated a combination of bevacizumab (10 mg/kg on days 8 and 22) with temozolomide (150 mg/m2 on days 1-7 and 15-21) in 36 patients with metastatic uveal melanoma (MUM).,The primary endpoint was the progression-free rate (PFR) at 6 months.,Using a modified 2-step Fleming plan, at least 10 of 35 patients were required to support a predefined PFR at 6 months of 40%.,Secondary objectives were progression-free survival (PFS), overall survival (OS), and safety; liver perfusion computed tomography (CT) for response imaging; and impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics.,First- and second-step analyses revealed nonprogression at 6 months in 3 of 17 and 8 of 35 patients, respectively.,Finally, the 6-month PFR was 23% (95% confidence interval [CI]: 10-39), with long-lasting stable disease in 5 patients (14%).,Median PFS and OS were 12 weeks and 10 months, respectively.,No unexpected toxicity occurred.,Liver perfusion CT imaging was not useful in assessing tumor response, and VEGF-A gene polymorphisms were not correlated with toxicity or survival.,In patients with MUM, a combination of bevacizumab plus temozolomide achieved a 6-month PFR of 23%.