1-s2.0-S0006291X19300580-main.pdf (1.34 MB)
1-s2.0-S0006291X19300580-main.pdf
journal contribution
posted on 2019-03-04, 21:28 authored by Kyuho Jeong, James Murphy, yelitza rodriguez, jun-sub kim, eun-young ahn, Ssang-Taek LimMalignant melanoma typically metastasizes to lymph nodes (LNs) as a primary or in-transit lesion before
secondary metastasis occurs, and LN biopsy is a common procedure to diagnose melanoma progression.
Since cancer metastasis is a complex process where various interactions between tumor cells and the
stroma play key roles in establishing metastatic lesions, the exact mechanisms underlying melanoma
metastasis to LNs remains unknown. It has been known that focal adhesion kinase (FAK) activity promotes
the expression of proinflammatory vascular cell adhesion molecule-1 (VCAM-1). As VCAM-1 is a
major receptor for a4 integrin and plays a key role in leukocyte recruitment, we reasoned that inhibition
of FAK activity may reduce VCAM-1 expression within LNs and thus reduce metastasis of a4 integrinexpressing
melanoma to LNs. First, we found that a pharmacological FAK inhibitor, PF-271, blocked tumor
necrosis factor-a (TNF-a)-mediated VCAM-1 expression on human dermal lymphatic endothelial
cells (HDLECs). In vitro, PF-271 significantly decreased B16F10 melanoma adhesion to and transmigration
through HDLECs compared to TNF-a treated cells. Furthermore, in vivo FAK inhibition by oral PF-271
administration reduced VCAM-1 expression in inguinal, cervical, and popliteal LNs compared to
vehicle treated mice. Finally, in a footpad metastasis model, B16F10 melanoma cells were injected into
the right footpad of C57BL/6 mice, and PF-271 (50 mg/kg, twice daily for 6 days) was orally administrated
after 1 week of tumor transplantation. While untreated mice exhibited significant metastatic melanoma
lesions in popliteal LNs, PF-271 treated mice showed only marginal melanoma metastasis. These results
support the possibility that FAK inhibitors may be a novel preventative option in melanoma metastasis
by blocking VCAM-1 expression in LNs.
secondary metastasis occurs, and LN biopsy is a common procedure to diagnose melanoma progression.
Since cancer metastasis is a complex process where various interactions between tumor cells and the
stroma play key roles in establishing metastatic lesions, the exact mechanisms underlying melanoma
metastasis to LNs remains unknown. It has been known that focal adhesion kinase (FAK) activity promotes
the expression of proinflammatory vascular cell adhesion molecule-1 (VCAM-1). As VCAM-1 is a
major receptor for a4 integrin and plays a key role in leukocyte recruitment, we reasoned that inhibition
of FAK activity may reduce VCAM-1 expression within LNs and thus reduce metastasis of a4 integrinexpressing
melanoma to LNs. First, we found that a pharmacological FAK inhibitor, PF-271, blocked tumor
necrosis factor-a (TNF-a)-mediated VCAM-1 expression on human dermal lymphatic endothelial
cells (HDLECs). In vitro, PF-271 significantly decreased B16F10 melanoma adhesion to and transmigration
through HDLECs compared to TNF-a treated cells. Furthermore, in vivo FAK inhibition by oral PF-271
administration reduced VCAM-1 expression in inguinal, cervical, and popliteal LNs compared to
vehicle treated mice. Finally, in a footpad metastasis model, B16F10 melanoma cells were injected into
the right footpad of C57BL/6 mice, and PF-271 (50 mg/kg, twice daily for 6 days) was orally administrated
after 1 week of tumor transplantation. While untreated mice exhibited significant metastatic melanoma
lesions in popliteal LNs, PF-271 treated mice showed only marginal melanoma metastasis. These results
support the possibility that FAK inhibitors may be a novel preventative option in melanoma metastasis
by blocking VCAM-1 expression in LNs.
