Affiliation of author: Women's Cancers Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
Correspondence to: Patricia S. Steeg, Ph.D., National Institutes of Health, Bldg. 10, Rm. 2A33, Bethesda, MD 20892 (e-mail: steeg{at}helix.nih.gov).
The metastasis field welcomes a new member, collapsin response mediator protein-1 (CRMP-1), which is reported to be a lung cancer invasion suppressor gene by Shih et al. (1) in this issue of the Journal. Shih et al. examined differential gene expression among a panel of lung carcinoma cell lines of varying invasive abilities by use of a 9600 complementary DNA microarray analysis. They wisely concentrated on the expression and function of one gene, CRMP-1. The less invasive lung cancer cell lines expressed relatively high levels of CRMP-1 messenger RNA (mRNA) and protein. Transfection of CRMP-1 into the highly invasive CL15 cell line reduced invasion through a Matrigel-coated membrane by approximately half. What makes this in vitro cell line observation intriguing is the attendant human lung tumor cohort study. The CRMP-1 mRNA levels of 80 non-small-cell lung carcinoma tumors were determined; patients with high CRMP-1-expressing tumors exhibited statistically significantly longer disease-free and overall survival. Thus, CRMP-1 represents an invasion suppressor with potential relevance to human disease. The data presented are thorough and convincing.
What is CRMP-1? A complex and incompletely understood set of signaling pathways connect CRMP to neural and possibly vascular development and are summarized below. CRMPs can function as inhibitors of axon extension in development, and one can hypothesize a similar signaling network in lung cancer invasion. What is intriguing is that, in development, cells of both the neural and vascular systems invade virtually every tissue. Suppressors of these pathways may, therefore, be of widespread applicability.
The CRMP family is best described in the regulation of axonal growth cone collapse. The CRMP family consists of four human members and has suffered the "name game," also being known as TUC, TOAD, Ulip, UNC, and DRG. In development, axons respond to environmental cues to extend; the leading edge sends out a growth cone in several directions (Fig. 1, A), and the appropriate orientation is realized by subsequent positive and negative signaling. A large family of Semaphorins (Sema), both secreted and membrane bound, is involved in this process. Semaphorin 3A (Sema3A) is a secreted member that participates in the repulsive (collapse) process by binding to a complex of plexin-1 and neuropilin-1 [Fig. 1
, B; reviewed in (2)]. Sema3A binds to neuropilin-1, and plexin-1 regulates the affinity of Sema binding. The plexins contain three domains with homology to c-met, the receptor for scatter factor-induced motility, but they lack the intrinsic tyrosine kinase activity of c-met (3). Intracellularly, invariant arginines identify a plexin domain with homology to guanosine triphosphatase-activating proteins; plexins are known to interact with Rho family members, and a dominant-negative Rac has been reported to prevent growth cone collapse. Several interesting motifs have been reported on the neuropilin portion of the Sema3A functional receptor. Both the extracellular complement and the coagulation factor domains contribute to the specificity of Sema binding. A short intracellular portion of neuropilin interacts with neuropilia-1-interacting protein, which is thought to recruit signal-transduction proteins and regulate protein clustering in membranes. Antibodies to neuropilin prevent growth cone collapse, and neuropilin-1/ mice fail to respond to Sema3A [reviewed in (4)]. The L1 cell adhesion molecule has been reported to bind neuropilin-1 and participate in Sema3A signaling (5). The CRMPs serve as intracellular mediators of growth cone collapse, because microinjection of antibodies to CRMP-62 (human CRMP-2) blocked growth cone collapse of dorsal root ganglia (6). Growth cone collapse is eventually achieved by filamentous (F)-actin depolymerization in the filopodia. Given this scenario, it is easy to envision a similar set of pathways resulting in suppression of invasion by lung tumor cells. In agreement with this model, Shih et al. (1) report that CMRP-1-transfected lung cancer cells have fewer F-actin-staining filopodia.
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Since invasion is a celebrated part of the metastatic process, the most important information remaining to be reported is whether the altered expression of CMRP-1 affects the in vivo metastatic potential of lung cancer cells. If suppressive, CRMP-1 will join a list of metastasis suppressor genes of interest to both the basic and the translational cancer fields [reviewed in (8)]. Several interesting observations suggest that this may be more complex than growth cone collapse and suppression of invasion. Neuropilin, part of the Sema3A receptor complex, also binds to KDR/flk-1 to form the active receptor for VEGF165 in angiogenesis [reviewed in (9)]. This interaction has been reported to mediate vascular branching morphogenesis in development and also endothelial cell chemotaxis and mitogenesis, of which the latter could potentially promote metastasis. Neuropilin-1 overexpression in the Dunning rat prostatic model resulted in larger, more vascular, and less apoptotic tumors in vivo (10). What is the role of semaphorins and CRMP-1 in this process? The only clue, recently published (11), maintains that the relative balance of neuropilin and KDR/flk-1 in neuroectodermal cells determines cellular motility, proliferation, and apoptotic responses, establishing an overlap of vascular pathways in a neural cell. Neuropilin is a busy protein. It also is expressed in bone marrow stromal cells; these cells bind both Sema3A and VEGF165, and at least one consequence is altered cytokine production (12). The effect of modulation of the immune response arm of the metastatic process must, therefore, be taken into consideration. We anxiously await elucidation of the role CRMP-1 in these systems.
One interesting hypothesis is that CRMP-1 determines only those inhibitory portions of the signaling pathways described, supported by the clear inverse correlation of lung tumor CRMP-1 level with patient clinical course. In vivo, certain of the pathways described may be more "dominant" than others and modulate metastatic potential. It remains plausible that CRMP-1 participates in other signaling pathways and that these pathways underlie the invasion/metastasis suppression. These same challenges of elucidating a biologic role and mechanistic functional pathway amid complexity and heterogeneity have dogged many other translational projects. The cancer scientists, patients, and advocates rightly insist that we resolve these problems, and both the basic metastasis and therapy fields await the next developments in CRMP-1 with intense interest.
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