ABSTRACT
Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B-mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2-CCR2 signaling or cathepsin B function significantly impaired PNI in vivo Correlative studies in human specimens demonstrated that cathepsin B-producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400-14. ©2017 AACR.
Subject(s)
Cathepsin B/metabolism , Chemokine CCL2/metabolism , Monocytes/metabolism , Pancreatic Neoplasms/metabolism , Peripheral Nerves/metabolism , Animals , Cell Line , Cell Line, Tumor , Chemokine CCL2/genetics , Humans , Macrophages/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , Monocytes/pathology , Neoplasm Invasiveness , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Peripheral Nerves/pathology , Receptors, CCR2/genetics , Receptors, CCR2/metabolism , Schwann Cells/metabolism , Transplantation, HeterologousSubject(s)
Ambulatory Surgical Procedures , Melanoma/surgery , Postoperative Complications/diagnosis , Pulmonary Embolism/diagnosis , Skin Neoplasms/surgery , Venous Thrombosis/diagnosis , Anticoagulants/therapeutic use , Humans , Male , Middle Aged , Postoperative Complications/drug therapy , Pulmonary Embolism/drug therapy , Risk Factors , Venous Thrombosis/drug therapyABSTRACT
Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression.
