Oncogenic BRAF is involved in various stages of melanoma development
The role of BRAF signaling in the pathogenesis of melanoma
Oncogenic BRAF mutations have been reported at various stages of melanoma, suggesting their role in disease progression along the clinical course, which includes initiation, malignant transformation, tumor progression, and metastasis (Figure 1). Note, however, that mutations in BRAF alone are not sufficient for oncogenesis since these mutations are also found in benign nevi.15
Figure 1 - BRAF mutations and melanoma progression
Development of cancer is a complex process that may involve mutations in various genes across multiple signaling pathways. For example, mutations in more than 1 gene may result in the development of melanoma. While mutations in the BRAF gene alone are not sufficient to initiate oncogenic signaling in melanoma, mutations in this gene can be found in different stages of the disease. This suggests that BRAF-mediated signaling plays a role in the initiation, progression, and spread of melanoma.15
Adapted with permission from Elsevier.15
Initiation and malignant transformation
The BRAFV600 mutation has been identified in precancerous lesions, suggesting involvement in the transformation of melanocytes. Some nevi that contain this mutation can result in melanoma, but it should be noted that not all nevi with this mutation are precancerous. Furthermore, while the BRAFV600 mutation contributes to the evolution of melanoma, studies have identified that mutations in other cellular proteins also play a role in this type of cancer.15,17
Studies have suggested a significant and necessary role for RAS-RAF signaling in the initiation of melanoma. The presence of activating BRAF mutations has been identified in up to 82% of benign nevi. Some experts have suggested that BRAF mutations in benign nevi may serve as markers of melanoma susceptibility in an individual.15,17
Although an activating BRAF mutation results in advantageous melanocyte proliferation, the activation of alternate pathways is necessary to fully transform quiescent melanocytes to a malignant state. For example, oncogenic BRAF has been reported to cooperate with the AKT pathway to promote melanoma growth.15,18
Tumor progression
Oncogenic BRAF signaling has been implicated in the progression of melanoma through the activation of tumor progression–related genes that are located downstream of oncogenic BRAF. These include, but are not limited to, the following15,19:
- MMP-1, an extracellular matrix protein15
- HIF-1α, a molecule that contributes to a microenvironment primed for tumor growth15
- BIM, a pro-apoptotic molecule that promotes further tumor cell survival19
At later stages of tumor development, oncogenic BRAF also contributes to angiogenesis by inducing autocrine vascular endothelial growth factor secretion. Cooperation with angiogenesis may promote further tumor survival and growth.15
BRAF's complex role in the activation of multiple signaling pathways allows for oncogenic BRAF to affect many molecules that promote the continual progression of melanoma.15
Metastasis: Oncogenic BRAF contributes to progression of malignancy
For decades, patients with metastatic melanoma have had a poor prognosis. Recent preclinical studies have suggested that oncogenic BRAF plays a vital role in promoting cell invasion and metastasis in melanoma. Oncogenic BRAF is involved in activities that include the following15,20:
- Activation of the transcription factor BRN2, which contributes to cell invasion and metastasis21
- Promotion of cytokine-mediated signaling, which results in invasive cellular behavior and development of metastasis22
- Coordination with silencing of the tumor suppressor gene PTEN, which has also been shown to contribute to metastasis in preclinical models17,23