RESUMO
The molecular mechanisms that regulate breast cancer cell (BCC) metastasis and proliferation within the leptomeninges (LM) are poorly understood, which limits the development of effective therapies. In this work, we show that BCCs in mice can invade the LM by abluminal migration along blood vessels that connect vertebral or calvarial bone marrow and meninges, bypassing the blood-brain barrier. This process is dependent on BCC engagement with vascular basement membrane laminin through expression of the neuronal pathfinding molecule integrin α6. Once in the LM, BCCs colocalize with perivascular meningeal macrophages and induce their expression of the prosurvival neurotrophin glial-derived neurotrophic factor (GDNF). Intrathecal GDNF blockade, macrophage-specific GDNF ablation, or deletion of the GDNF receptor neural cell adhesion molecule (NCAM) from BCCs inhibits breast cancer growth within the LM. These data suggest integrin α6 and the GDNF signaling axis as new therapeutic targets against breast cancer LM metastasis.
Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Integrina alfa6 , Neoplasias Meníngeas , Meninges , Vias Neurais , Animais , Feminino , Humanos , Camundongos , Membrana Basal/metabolismo , Neoplasias Ósseas/secundário , Neoplasias Ósseas/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Integrina alfa6/metabolismo , Laminina/metabolismo , Macrófagos/metabolismo , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/secundário , Meninges/patologia , Invasividade Neoplásica , Moléculas de Adesão de Célula Nervosa/metabolismo , Moléculas de Adesão de Célula Nervosa/genética , Transdução de Sinais , Vias Neurais/metabolismo , Camundongos SCID , Camundongos KnockoutRESUMO
T-cell-rich angiomatoid polypoid pseudolymphoma (TRAPP) is a rare and recently defined entity, conceptualized just over a decade ago. Recognition of TRAPP is important because it can be clinically and microscopically confused with low-grade cutaneous lymphomas and other vascular proliferations. We report a case of a 28-year-old male with a solitary 1.2 cm red polypoid papule on the middle posterior base of the neck. The histopathological examination revealed a well-circumscribed dermal nodular proliferation of banal-appearing lymphovascular spaces with plump endothelial cells. Immunohistochemical analysis showed a T-cell-rich infiltrate. The clinical-pathological differential diagnosis for TRAPP includes pyogenic granuloma, angiolymphoid hyperplasia (epithelioid hemangioma), acral pseudolymphomatous angiokeratoma of children, cutaneous lymphoid hyperplasia, and low-grade cutaneous lymphomas and lymphoproliferative disorders. We review the literature and discuss the key differentiating features between TRAPP and its common differential diagnoses.
