Neural Cell Adhesion Molecule CD56 Research Articles

The 140-kD Isoform of CD56 (NCAM1) Directs the Molecular Pathogenesis of Ischemic Cardiomyopathy

Despite recent advances in understanding the relevance of cell adhesion-related signaling in the pathogenesis of ischemic cardiomyopathy (ICM) in animal models, substantial questions remain unanswered in the human setting. We have previously shown that the neural cell adhesion molecule CD56 [neural cell adhesion molecule (NCAM1)] is specifically overexpressed in ICM; it was the aim of the current study to further elucidate the role of CD56 in the pathogenesis of human ICM. We used quantitative real-time PCR and IHC in human ICM and a rat model of coronary obstruction to demonstrate that CD56(140kD), the only extraneuronally expressed NCAM1 isoform with a cytoplasmic protein domain capable of inducing intracellular signaling, is the only up-regulated CD56 isoform in failing cardiomyocytes in human ICM invivo. In subsequent analyses of the cellular effects of CD56(140kD) overexpression in the development of ICM using differential whole transcriptome expression analyses and functional invitro cardiomyocyte cell culture assays, we further show that the up-regulation of CD56(140kD) is associated with profound gene expression changes, increased apoptosis, and reduced Ca(2+) signaling in failing human cardiomyocytes. Because apoptosis and Ca(2+)-related sarcomeric dysfunction are molecular hallmarks of ICM in humans, our results provide strong evidence that CD56(140kD) up-regulation plays a pivotal role in the pathogenesis of ICM and may be a target for future immunotherapeutic strategies in the treatment of this common and often fatal disease.

Specific Detection of CD56 (NCAM) Isoforms for the Identification of Aggressive Malignant Neoplasms with Progressive Development

Alternative splicing of transcripts from many cancer-associated genes is believed to play a major role in carcinogenesis as well as in tumor progression. Alternative splicing of one such gene, the neural cell adhesion molecule CD56 (NCAM), impacts the progression, inadequate therapeutic response, and reduced total survival of patients who suffer from numerous malignant neoplasms. Although previous investigations have determined that CD56 exists in three major isoforms (CD56(120kD), CD56(140kD), and CD56(180kD)) with individual structural and functional properties, neither the expression profiles nor the functional relevance of these isoforms in malignant tumors have been consistently investigated. Using new quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) strategies and novel CD56 isoform-specific antibodies, CD56(140kD) was shown to be exclusively expressed in a number of highly malignant CD56(+) neoplasms and was associated with the progression of CD56(+) precursor lesions of unclear malignant potential. Moreover, only CD56(140kD) induced antiapoptotic/proliferative pathways and specifically phosphorylated calcium-dependent kinases that are relevant for tumorigenesis. We conclude, therefore, that the specific detection of CD56 isoforms will help to elucidate their individual functions in the pathogenesis and progression of malignant neoplasms and may have a positive impact on the development of CD56-based immunotherapeutic strategies.

A single institution experience with neuroendocrine tumors

15164 Background: ABSTRACT Introduction: . The aim of this study was to analyze demographic, therapy, tumor and clinical outcomes of all cases of neuroendocrine cancer at a tertiary cancer and determine the the markers that may better correlate with outcomes than histologic grade. Patients and Methods: With IRB approval , 126 charts with a diagnosis of neuroendocrine carcinoma were identified between 1–1-1999 and 1–1-2004. Ninety-five cases were selected on the basis of complete availability of baseline, therapy and at least one time point of followup data. Patient demographics, therapy details, TNM stage, tumor marker and survival data were collected. Tumors were graded as well, moderate and poorly differentiated and by site of origin. We attempted to correlate the outcome with NCAM(neural cell adhesion molecule-CD56) status, which is a homophylic binding glycoprotein to have a role in cell adhesion. Descriptive statistics and frequency tables were used to describe the data and kaplan meier methods were used to estimate the median survival. Results: There were 28 patients with lung primaries, 25 had primaries in the gut (extra pancreatic),11 had pancreatic primaries, 31 cases had unknown primaries or primaries at sites other than the lungs or the gastrointestinal tract. The estimated median survival for the whole sample was 34 months.(95% C I :20,54) and the 2 year survival rate was 55.3 %.The estimated median survival for CD56 positive group was 11 months(95% C.I :3,38) and that for CD 56 unknown group was 36(95% C .I :20,n/a). A significant difference in survival between CD56 positive group and CD56 unknown was found,based on log-rank test>(P=.02). Baseline characteristics were as follows: M:F 48:47; 19 were well differentiated, 4 were moderately differentiated and 36 of 95 tumors were poorly differentiated, the differentiation was not known in 36 cases. Surgery with curative intent was done in 52 of the patients(54.74%) and 52 received (54.74%)t chemotherapy, 4 patients(4.2%) received chemoembolization and 2 patients(2.1%) received local ablative treatments. Conclusion: These data summarize our instutions experience with this rare malignancy. In our data survival was as expected in the literature and further investigation of the CD 56 status of all patients is underway. No significant financial relationships to disclose.

Neural cell adhesion molecule (CD56)‐positive B‐cell lymphoma

Expression of neural cell-adhesion molecule CD56 is a rare event in B-cell lymphoma. We described four cases of CD56-positive B-cell lymphoma, including follicular lymphoma and diffuse large B-cell lymphoma. These lymphoma cells expressed CD10 and bcl-6, which suggests germinal center-stage phenotype. Immunohistochemistry showed that CD56-positive cells aggregated and displayed a cohesive growth pattern, indicating that homotypic adhesion through the molecules might affect the manner of tumor growth and expansion. Although CD56 expression level varies among the cases, this molecule might play some roles in the manner of growth and expansion of CD56-positive B-cell lymphomas.

Acute Myeloid Leukemia Disguised as a Solid Tumor

Granulocytic sarcomas, or extramedullary collections of immature leukemic cells, are observed in a small precentage of myeloid leukemias. The t(8;21) seems to have a higher association with granulocytic sarcoma. Although patients with t(8;21) generally have a more favorable prognosis, the presence of these sarcomas makes their course less favorable. We report a case of a woman with acute myeloid leukemia M2 who presented with 5 sites of extramedullary involvement including pleural fluid involvement which is exceedingly rare. She presented with weakness and shortness of breath. She was initially evaluated and treated for an upper respiratory tract infection. Later work-up revealed the presence of circulating blasts on peripheral blood smear. Bone marow biopsy showed 100% cellularity with blast forms comprising > 80% of those. A computed tomography scan was done, which showed a paratracheal mass, an anterior mediastinal mass, a perinephric soft tissue density and a pleural effusion which was positive for malignant cells by cytology. A superior extraconal mass was found in the left orbit on magnetic resonance imaging. The patient received induction chemotherapy after which repeat scans have shown a resolution of the pleural effusion and improvement in the size of the other granulocytic sarcoma. A review of granulocytic sarcomas shows that they can occur in numerous anatomic sites. There appears to be an association with the neural cell adhesion molecule CD56. The prognosis is worse in those with granulocytic sarcoma. Stem cell transplantation is considered an early option thought not clearly defined at this point.

Increased subpopulations of CD16+ and CD56+ blood monocytes in patients with active Crohnʼs disease

Circulating monocytes may be subdivided according to the presence or absence of the Fcgamma receptor CD16 and the neural cell adhesion molecule CD56. Monocytes classified into these subpopulations are characterized by distinct phenotypic and functional features. We hypothesized that patients with active Crohn's disease differ in their peripheral monocyte subpopulations. Using flow cytometry we investigated the expression of CD16 and CD56 on circulating monocytes in 11 patients with active Crohn's disease and 11 controls. These monocyte subpopulations were then analyzed for expression of the chemokine receptor fractalkine, CX(3)CR1, and the monocyte chemoattractant protein-1, CCR2. We found a median 3.7-fold increase in the number of CD16(+) monocytes related to the population with high expression of the pattern recognition receptor CD14 compared to that in the controls (P < 0.001). By studying the percentage of monocytes expressing CX(3)CR1, and their relative fluorescence intensity (RFI), we found significant differences, with both the highest percentage and the highest RFI in the CD14(low)CD16(+) subpopulation, whereas the CD14(high)CD16(+) subgroup represented an intermediate population. Inversely, CCR2 expression was highest in the populations with high expression of CD14, whereas the CD14(low)CD16(+) subpopulation showed the lowest percentage and the lowest RFI for CCR2. We found the percentage of CD14(+)CD56(+) monocytes in patients with active Crohn's disease to be increased 2.7 times compared to the controls (P = 0.011). These results show that subsets of peripheral monocytes with a more mature phenotype are expanded in patients with active Crohn's disease.

Detection of FGFR3 by Immunohistochemistry in Multiple Myeloma Is Highly Predictive of t(4;14) by FISH and Is Associated with CD56 (NCAM1) Expression.

Recent studies have demonstrated that neural cell adhesion molecule CD56 (NCAM1) is involved in multiple adhesive interactions with several different classes of ligands on the cell surface and in the extracellular matrix. One of these ligands is fibroblast growth factor receptor (FGFR) family. While a direct interaction between CD56 (NCAM1) and FGFR3 is yet to be reported we have speculated that such interaction might exist in myeloma cells with aberrant FGFR3 expression. In order to test this hypothesis we have retrospectively examined the presence of t(4;14) in 127 multiple myeloma samples and its correlation with the presence of deletion 13 by FISH; FGFR3 and cyclin D1 expression by immunohistochemistry and CD56 expression as determined by flow cytometry. FISH detected t(4;14) in 32 (25.1%) of 127 MM patient specimens. 71.4% of t(4;14) positive samples were found to have deletion of chromosome 13, in contrast to only 34% in t(4;14) negative samples. Aberrant expression of FGFR3 was detected by immunohistochemistry in 14/21 or 66.7% of t(4;14) positive samples. No expression of FGFR3 was detected in 10 t(4;14) negative samples. As expected low Cyclin D1 expression by IHC was detected in t(4;14) positive samples (5/21 or 23.8%). More importantly all samples positive for FGFR3 by IHC were CD56 positive (14/14 or 100%) and in 21/22 (95.5%) of t(4;14) positive in contrast to 62% in t(4;14) samples. Further work is currently being conducted in order to examine the downstream signaling pathways that might be activated as a result of such possible interaction.

A surrogate marker profile for PML/RAR alpha expressing acute promyelocytic leukemia and the association of immunophenotypic markers with morphologic and molecular subtypes.

The availability of genotype-specific therapy for PML/RAR alpha(pos) acute promyelocytic leukemia (APL) requires that this disease be precisely diagnosed. Immunophenotypic characteristics heretofore proclaimed as reliably characterizing APL (HLA-DR(low), CD34(low), P-glycoprotein(low) myeloid phenotype) do not differentiate from APL-like immune profiles unassociated with the PML/RAR alpha fusion transcript. To establish a surrogate marker profile for APL, we explored 19 potentially predictive markers compared with differentiated acute myeloid leukemia using the classification tree approach with recursive partitioning. In a test group of 58 APL patients, the most predictive immune profile was HLA-DR(low), CD11a(low) (alpha(L) subunit of the leukocyte integrin LFA-1), CD18(low) (beta(2) subunit of LFA-1). APL cells always expressed CD117 (c-kit) but lacked the progenitor antigen CD133 and the more mature myeloid antigen, CD11b (alpha(M) leukocyte integrin). This antigen pattern was validated in 90 additional APL patients. M3v APLs (n = 30) had more leukemic promyelocytes expressing the T-cell antigen, CD2 (P < 0.0001) or the stem cell marker, CD34 (P = 0.0003) and demonstrated higher fluorescence intensity for the binding of antibody to the common leukocyte antigen, CD45 (P = 0.0008) than M3 (n = 102). S-form APL (n = 45) had a higher percent of cells expressing CD2 or CD34 (P < 0.0001 for both) or the neural cell adhesion molecule CD56 (P = 0.001) than L-form APL (n = 66). PML/RAR alpha(pos) APL cells typically lack leukocyte integrins. HLA-DR(low), CD11a(low), CD18(low) is a reliable surrogate antigen expression profile for PML/RAR alpha(pos) APL, irrespective of morphology and transcript isoform.

Expression of the neural cell adhesion molecule CD56 is not associated with P-glycoprotein overexpression in core-binding factor acute myeloid leukemia

Acute myeloid leukemia (AML) with rearrangement of the core-binding factor (CBF) α or β subunit gene has a favorable prognosis, but CD56 expression in CBFα-AML is associated with short disease-free survival. A proposed mechanism is overexpression of the multidrug resistance (MDR) protein P-glycoprotein (Pgp). CD56 expression, Pgp expression and function, and expression of the additional MDR proteins multidrug resistance protein-1 (MRP-1), lung resistance protein (LRP) and breast cancer resistance protein (BCRP) were studied in pretreatment blasts from 25 CBF-AML patients. CD56 expression was frequent in CBFα but rare in CBFβ, and Pgp expression and function were frequent in both subtypes. CD56 expression did not correlate with Pgp expression or function, nor with expression of the other MDR proteins. Treatment failure associated with CD56 expression in CBFα-AML is not likely attributable to Pgp.

Expression of the Neural Cell Adhesion Molecule CD56 Is Associated With Short Remission Duration and Survival in Acute Myeloid Leukemia With t(8; 21)(q22; q22)

Although acute myeloid leukemia (AML) with t(8;21) (q22;q22) is associated with a high complete remission (CR) rate and prolonged disease-free survival, treatment outcome is not universally favorable. Identifying factors that predict for treatment outcome might allow therapy to be optimized based on risk. AML with t(8;21) has a distinctive immunophenotype, characterized by expression of the myeloid and stem cell antigens CD13, CD15, CD34, and HLADr, and frequent expression of the B-cell antigen CD19 and the neural cell adhesion molecule CD56, a natural killer cell/stem cell antigen. Because CD56 expression has been associated with both extramedullary leukemia and multidrug resistance, we sought to correlate CD56 expression with treatment outcome in AML with t(8;21). Pretreatment leukemia cells from 29 adult de novo AML patients with t(8;21) treated on Cancer and Leukemia Group B (CALGB) protocols were immunophenotyped by multiparameter flow cytometry as part of a prospective immunophenotyping study of adult AML (CALGB 8361). CD56 was expressed in 16 cases (55%). There was no correlation between CD56 expression and age, sex, white blood cell count, granulocyte count, the presence of additional cytogenetic abnormalities, or the presence of extramedullary disease at diagnosis. The CR rate to standard-dose cytarabine and daunorubicin was similar for cases with and without CD56 expression (88% v 92%; P = 1.0). Post-CR therapy included at least one course of high-dose cytarabine in 24 of 26 patients who achieved CR; numbers of courses administered were similar in cases with and without CD56 expression. Although post-CR therapy did not differ, CR duration was significantly shorter in cases with CD56 expression compared with those without (median, 8.7 months v not reached; P = .01), as was survival (median, 16.5 months v not reached; P = .008). We conclude that CD56 expression in AML with t(8;21) is associated with significantly shorter CR duration and survival. Our results suggest that CD56 expression may be useful in stratifying therapy for this subtype of AML.

Expression of the Neural Cell Adhesion Molecule CD56 Is Associated With Short Remission Duration and Survival in Acute Myeloid Leukemia With t(8; 21)(q22; q22)

AbstractAlthough acute myeloid leukemia (AML) with t(8; 21) (q22; q22) is associated with a high complete remission (CR) rate and prolonged disease-free survival, treatment outcome is not universally favorable. Identifying factors that predict for treatment outcome might allow therapy to be optimized based on risk. AML with t(8; 21) has a distinctive immunophenotype, characterized by expression of the myeloid and stem cell antigens CD13, CD15, CD34, and HLADr, and frequent expression of the B-cell antigen CD19 and the neural cell adhesion molecule CD56, a natural killer cell/stem cell antigen. Because CD56 expression has been associated with both extramedullary leukemia and multidrug resistance, we sought to correlate CD56 expression with treatment outcome in AML with t(8; 21). Pretreatment leukemia cells from 29 adult de novo AML patients with t(8; 21) treated on Cancer and Leukemia Group B (CALGB) protocols were immunophenotyped by multiparameter flow cytometry as part of a prospective immunophenotyping study of adult AML (CALGB 8361). CD56 was expressed in 16 cases (55%). There was no correlation between CD56 expression and age, sex, white blood cell count, granulocyte count, the presence of additional cytogenetic abnormalities, or the presence of extramedullary disease at diagnosis. The CR rate to standard-dose cytarabine and daunorubicin was similar for cases with and without CD56 expression (88% v 92%; P = 1.0). Post-CR therapy included at least one course of high-dose cytarabine in 24 of 26 patients who achieved CR; numbers of courses administered were similar in cases with and without CD56 expression. Although post-CR therapy did not differ, CR duration was significantly shorter in cases with CD56 expression compared with those without (median, 8.7 months v not reached; P = .01), as was survival (median, 16.5 months v not reached; P = .008). We conclude that CD56 expression in AML with t(8; 21) is associated with significantly shorter CR duration and survival. Our results suggest that CD56 expression may be useful in stratifying therapy for this subtype of AML.