Extensive Expression of Collapsin Response Mediator Protein 5 (CRMP5) is a Specific Marker of High-grade Lung Neuroendocrine Carcinoma

Abstract

The diagnosis of high-grade neuroendocrine tumors has strong clinical relevance because it identifies patients at higher risk of an unfavorable outcome who should receive multimodal treatment. However, these tumors can be mistaken for poorly differentiated nonsmall cell carcinoma or carcinoid lung tumors. In fact, no immunohistochemical marker can currently distinguish between histologic lung subtypes. Because the collapsin response mediator protein (CRMP) family is involved in an autoimmune disease associated with small cell lung carcinoma, we explored the relationship between CRMP5 expression and lung tumor behavior. Using World Health Organization morphologic criteria, 123 lung neuroendocrine tumors and 41 randomly selected non-neuroendocrine tumors were classified. CRMP5 protein expression in tumors, metastases, and healthy lung tissue was assessed using immunostaining method. Strong and extensive CRMP5 expression was seen in 98.6% of high-grade neuroendocrine lung tumors, including small cell lung carcinoma and large cell lung neuroendocrine carcinoma, but not in any of the squamous cell carcinomas or lung adenocarcinomas in our series. In contrast, the majority of low-grade neuroendocrine lung tumors were negative for CRMP5 staining, although weak CRMP5 expression was seen in some, with 2 different staining patterns of either scattered positive cells or small foci of positive cells. Our findings point at CRMP5 as a novel marker for routine pathologic evaluation of lung tumors surgical samples in distinguishing between highly aggressive neuroendocrine carcinoma and the other lung cancers.

CRMP5 Regulates Generation and Survival of Newborn Neurons in Olfactory and Hippocampal Neurogenic Areas of the Adult Mouse Brain

“…This original finding is in favor of a role of CRMP5 in the transition phase between proliferative and non-proliferative stages, suggesting that CRMP5 might play an active role in adult neurogenesis by taking part to the repression of proliferation and/or to the induction of the first stages of neuronal differentiation. The high expression level of CRMP5 in aggressive neuroendocrine tumors [23] highlights the likely involvement of this protein in the balance between proliferation and differentiation in different cell types and in both physiological and pathological conditions.…”

CRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch-Dependent Signaling

“…Human GBM biopsies fixed in AFA were stained using Ventana Ultraview peroxydase system combined with the following primary antibodies: anti-CRMP5 polyclonal rabbit antibody (1:100; refs. 10,14); anti-Hes1 (1:30; Cell Signaling Technology, 11988); and anti-Notch1 (1:50; Abcam ab52627).…”

“…1B). Subcellular fractionation of GBM extracts and immunolocalization using a CRMP5 polyclonal antibody demonstrated cytoplasmic and nuclear forms of CRMP5 in GBM tumors, cell lines and only in GBM_SC1 xenograft ( CRMP5 expression in GBM predicts lower patient survival and is related to tumor proliferation CRMP5 protein immunohistochemical expression in GBM tumors was obtained from 183 GBM biopsies using a CRMP5 polyclonal antibody previously validated with lung tumor biopsies (14). Two CRMP5 expression patterns emerged: low CRMP5 expression (CRMP5 LOW : N ¼ 23, 12.6%) was characterized by weak, heterogeneously dispersed CRMP5 staining in 0% to 10% of cells, and high CRMP5 expression (CRMP5 HIGH : N ¼ 160, 87%) was characterized by highly diffuse cytoplasmic staining of CRMP5 in approximately 90% of tumor cells ( Fig.…”

“…We previously described that CRMP5 protein expression in peripheral tumors causes the development of paraneoplastic neurologic syndromes (10,12,13). Furthermore, we proposed CRMP5 protein expression as a marker for high-grade lung neuroendocrine carcinomas, a very aggressive and treatmentresistant lung tumor (14) and observed its expression in GBM cells (15). However, no specific role has been proposed for CRMP5 protein in GBM, or, more broadly, in the cancer process.…”

Upregulation of CRMP4, a new prostate cancer metastasis suppressor gene, inhibits tumor growth in a nude mouse intratibial injection model

“…Both GSK-3β and WAVE-1 were involved in CRMP mediated axon outgrowth, indicating CRMP has diverse functions in different cellular processes. Other CRMP family members involved in cancer include CRMP2, CRMP4 and CRMP5, all were reported associated with different cancer cell migration, invasion, differentiation and clinical outcome in certain tumor types (16)(17)(18)(19). In our previous study (20), we first identified CRMP4 as a prostate cancer metastasis suppressor factor by proteomics approach and verified that CRMP4 suppress prostate cancer cell line proliferation and invasion in vitro and the downregulation of CRMP4 in metastatic tumor may be due to the methylation of the CpG island within the promoter region of the CRMP4 gene.…”