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Midkine is highly expressed in neuroblastoma tissues
Abstract
Neuroblastoma (NBL) is a tumor from neural crest cells, and is the most frequent solid tumor in children. Midkine (MK) is a pleiotropin analogon, which is frequently expressed in neuronal and epithelial tumors and is a marker for a poor clinical outcome. The aims of this study were to assess MK expression in NBL and investigate the correlation with clinical outcome.
Fifty-six specimens of NBL were stained for MK on a tissue microarray by immunohistochemistry (IHC). Fresh frozen tumor tissues were used for RNA isolation, and RT-PCR analysis for MK-mRNA expression was performed. Survival data, risk factors and disease stages were correlated with MK status assessed by IHC and RT-PCR analysis.
MK-mRNA expression was found in the majority of the tumor tissues (75%), whereas MK protein could be detected only in 46% of the NBL by IHC. No correlation of MK status with survival, risk factors or disease stage was observed.
A majority of NBL express MK-mRNA, whereas not all MK mRNA positive tumors showed also a positive MK IHC staining. The high expression of MK-mRNA expression might present a promising target for new adenovirus-based gene therapeutic approaches for the treatment of NBL.
... Interestingly, these cytokines are both expressed in neuroblastoma (21,22). ...
... In accordance with previous studies (21,22), we found that the two postulated ALK ligands, pleiotrophin (PTN) (17) and midkine (MDK) (18), are frequently expressed in neuroblastoma (in 58% and 79% of tumors, respectively) and are thus likely to represent a major mechanism of ALK activation in neuroblastoma. Several observations indicated that at least MDK is able for ALK in different cell types, including sympathetic neurons (18,40,41). ...
Neuroblastoma, including high-risk cases, show a good initial response to chemotherapy but will frequently become resistant to treatment. Topoisomerase I inhibitors represent an important therapeutic option for refractory neuroblastoma. To study the reisitance to topoisomerase I inhibitors acquired in a therapeutic setting, we developed in vivo a resistant model to irinotecan (CPT-11). Chemoresistance is known as a multifactorial phenomenon. We have therefore used several approaches to better characterize mechanisms leading to resistance in our model. A genomic approach enabled us to identify the deregulation of a signaling pathway, constituted with a receptor (ALK) and two lignads (PTN and MDK). While ALK is decsribed as a major neuroblastoma predisposition gene, mainly through activating mutations, we demonstrated that the activation of ALK occurs via mechanisms others than mutation in a large majority of cases. Moreover ALK activation is an important event in the initiation of the disease. However, we couldn’t prouve the implication of the receptor in the progression of the disease or in its response to treatment. It seems that the regulation of ALK is complex and its precise role in the progression of neuroblastoma remains to be precisely defined. Nevertheless, we have demonstrated the importance of MDK, one of ALK ligands in the regulation of the expression and activation of ALK as well as in the control of the neuroblastoma cells survival. The inhibition of the cytokine, MDK represents an interesting therapeutic strategy, complementary to anti-ALK therapies, currently in clinical development in neuroblastoma. On another hand, the phenotypic characterization of the model, showed an alteration of the signaling of DNA damage and an increased genomic instability in the resistant tumors. Those tumors also harbor a modification in the cell cycle progression, particularly an increased proportion of quiescent cells. Finally, this work enables us to identify several resistance mechanism that represent markers of response to chemotherapy and relevant therapeutic targets in neuroblastoma.
... Whereas S-MK is a good marker of prognosis in many cancers, its level does not invariably correlate with tissue MK expression. [9][10][11][12][13][25][26][27][28] Recently an elevated S-MK level is detected in CRC. 19 However, the relation between S-MK and CRC prognosis is not being documented. ...
A AB BS ST TR RA AC CT T O Ob bj je ec ct ti iv ve e: : Midkine (MK) is a heparin-binding growth factor that plays important roles in cell transformation and angiogenesis. Recent studies indicated that MK was involved in genesis and development of colorectal carcinomas (CRC). However in these tumors the relationship among MK expression, angiogenesis and prognosis has not been evaluated. The purpose of this study was to investigate whether MK expression was associated with angiogenesis and survival in patients with CRC. M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : Tumor specimens from 61 patients diagnosed as CRC were included in this study. Serial sections from paraffin embedded tissues were stained with anti-mid-kine and anti-CD34 antibodies. Angiogenesis was assessed as microvessel density (MVD). Chi-square test, Kaplan-Meier method and Cox regression analysis were used for statistical analysis. R Re es su ul lt ts s: : MK expression was observed in 36 of the cases. Non-neoplastic mucosa was consistently negative. Any relationship was not observed between MK expression and clinicopathologic parameters, so MK expression failed to predict tumor behavior. Moreover MK expression was not associated with MVD. On the other hand the prognosis was significantly worse in patients with high MVD (>5.8). Survival analysis revealed that although MK expression had no impact on prognosis, MVD was an independent prognostic variable. C Co on nc cl lu us si io on n: : Our results revealed that MK expression has no prognos-tic relevance in CRC. However MVD could be reliable indicator of prognosis. Although our data needs to be clarified with further molecular studies, the lack of correlation between MK expression and MVD suggests that MK has no impact on CRC related angiogenesis. K Ke ey y W Wo or rd ds s: : Colorectal neoplasms; midkine; prognosis Ö ÖZ ZE ET T A Am ma aç ç: : Midkin (MK) hücre transformasyonu ve anjiogenezde önemli bir rol alan 'heparin-bağlayıcı-büyüme faktörü' dür. Yakın geçmişde yapılan çalışmalarda MK'nin kolorektal karsinom oluşumunda (KRK) ve gelişiminde rol oynadığı gösterilmiştir. Ancak bu tümörlerde MK ekspres-yonu, anjiogenez ve hastalığın seyri arasındaki ilişki araştırılmamıştır. Bu çalışmanın amacı KRK olgularında MK ekspresyonunun, anjiogenez ve prognoz ile ilişkisinin olup olmadığının araştırıl-masıdır. G Ge er re eç ç v ve e Y Yö ön nt te em ml le er r: : Bu çalışmaya KRK tanısı alan 61 hastanın tümör spesimeni dahil edildi. Parafin kesitler anti-midkine ve anti-CD34 antikorları ile boyandı. Anjiogenezis mikroda-mar yoğunluğu (MVD) olarak değerlendirildi. İstatistiksel analiz için Ki-kare testi, Kaplan-Meier metodu, ve Cox regresyon analizi uygulandı. B Bu ul lg gu ul la ar r: : MK ekspresyonu 36 olguda gözlendi. Non neoplastik mukoza daima negatifti. MK ekspresyonu ile klinik ve patolojik parametreler arasında hiçbir ilişki gözlenmedi. Bu nedenle tümör davranışını belirlemede MK ekspresyonu yetersizdi. Dahası MK ekspresyonu ile MVD arasında ilişki bulunmadı. Diğer bir yandan MVD'si yüksek olan (>5,8) hastalarda prognoz belirgin olarak kötüydü. Her ne kadar MK ekspresyonunun hastalığın seyrine bir etkisi olmasa da çok değişkenli sağkalım analizinde MVD'nin bağımsız prognostik deği-şken olduğu gözlendi. S So on nu uç ç: : Bulgularımız KRK'da MK ekspresyonunun prognostik bir değeri ol-madığını göstermiştir. Buna karşın MVD hastalığın seyrinin belirlenmesinde önemli bir belirteçtir. Her ne kadar bulgularımızın daha ileri moleküler çalışmalar ile desteklenmesi gerekse de, MK eks-presyonu ve MVD arasında bir ilişkinin gözlenmemesi MK'nin KRK ile ilişkili anjiogenezde rolü ol-madığını düşündürmektedir. A An na ah ht ta ar r K Ke el li im me el le er r: : Kolorektal tümörler; midkine; prognoz T Tu ur rk ki iy ye e K Kl li in ni ik kl le er ri i J J G Ga as st tr ro oe en nt te er ro oh he ep pa at to ol l 2 20 01 12 2; ;1 19 9((1 1)): :1 15 5-2 22 2
... However, besides Alk (Stoica et al., 2002), a number of additional receptor types have been identified for Mk, including PTP (Maeda et al., 1999), integrins (Muramatsu et al., 2004), Notch2 (Huang et al., 2008), LDL receptor-related protein (Muramatsu et al., 2000) and neuroglycan C (Ichihara-Tanaka et al., 2006). Both MK and PTN are expressed at high levels in neuroblastoma, but only MK expression correlates with aggressive NB (Fiegel et al., 2008; Nakagawara et al., 1995). Mk-deficient mice have not been analyzed specifically for defects in SG development (Nakamura et al., 1998). ...
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and arises from cells of the developing sympathoadrenergic lineage. Activating mutations in the gene encoding the ALK tyrosine kinase receptor predispose for NB. Here, we focus on the normal function of Alk signaling in the control of sympathetic neuron proliferation, as well as on the effects of mutant ALK. Forced expression of wild-type ALK and NB-related constitutively active ALK mutants in cultures of proliferating immature sympathetic neurons results in a strong proliferation increase, whereas Alk knockdown and pharmacological inhibition of Alk activity decrease proliferation. Alk activation upregulates NMyc and trkB and maintains Alk expression by an autoregulatory mechanism involving Hand2. The Alk-ligand Midkine (Mk) is expressed in immature sympathetic neurons and in vivo inhibition of Alk signaling by virus-mediated shRNA knockdown of Alk and Mk leads to strongly reduced sympathetic neuron proliferation. Taken together, these results demonstrate that the extent and timing of sympathetic neurogenesis is controlled by Mk/Alk signaling. The predisposition for NB caused by activating ALK mutations may thus be explained by aberrations of normal neurogenesis, i.e. elevated and sustained Alk signaling and increased NMyc expression.
... Mdk is also implicated in the development of cancer because of its mitogenic effect [10,11], promotion of angiogenesis [12], anti-apoptotic activity [13,14], fibrinolytic activity [15], and transforming activity [16]. Mdk is overexpressed in various human cancers, including esophageal [17], gastrointestinal [18], hepatocellular [19], lung [20], breast [21], pancreatic carcinoma [22,23], Wilm's tumor [24], and neuroblastoma [25], when compared with adjacent normal tissues. In contrast, Mdk expression in normal human adult tissues is quite limited, with moderate expression in the kidneys and weak expression in lungs, colon, and thyroid gland [8,18,21,24]. ...
Malignant mesothelioma is a highly aggressive tumor with poor prognosis. We hypothesized that the tumor-specific midkine (Mdk) promoter could confer transcriptional targeting to oncolytic adenoviruses for effective treatment of malignant mesothelioma.
We analysed Mdk expression by quantitative reverse transcription-polymerase chain reaction in six human mesothelioma cell lines, and tested Mdk promoter activity by luciferase reporter assay. On the basis of these data, we constructed a replication-selective oncolytic adenovirus designated AdMdk-E1-iresTK. This virus contains a Mdk promoter-driven adenoviral E1 gene and herpes simplex virus-thymidine kinase (TK) suicide gene and cytomagalovirus promoter-driven enhanced green fluorescent protein marker gene. Selectivity of viral replication and cytolysis were characterized in normal versus mesothelioma cells in vitro, and intratumoral spread and antitumor efficacy were investigated in vivo.
Mdk promoter activity was restricted in normal cells, but highly activated in mesothelioma cell lines. AdMdk-E1-iresTK was seen to efficiently replicate, produce viral progeny and spread in multiple mesothelioma cell lines. Lytic spread of AdMdk-E1-iresTK mediated the efficient killing of these mesothelioma cells, and its in vitro cytocidal effect was significantly enhanced by treatment with the prodrug, ganciclovir. Intratumoral injection of AdMdk-E1-iresTK caused complete regression of MESO4 and MSTO human mesothelioma xenografts in athymic mice. In vivo fluorescence imaging demonstrated intratumoral spread of AdMdk-E1-iresTK-derived signals, which vanished after tumor eradication.
These data indicate that transcriptional targeting of viral replication by the Mdk promoter represents a promising general strategy for oncolytic virotherapy of cancers with up-regulated Mdk expression, including malignant mesothelioma.
... 9,13 It has been proven to be involved in tumorigenesis of neuroblastoma, astrocytoma, and malignant peripheral nerve sheath tumors (MPNSTs). [14][15][16][17] Since MK is a secretory protein, it can be detected in the peripheral blood of patients with MK overexpressing tumors. It has been reported that elevated serum MK (S-MK) levels decrease after removal of tumors. ...
A previous study identified midkine (MK) expression in primary gastrointestinal stromal tumor (GIST) as a prognostic marker. The aim of the current study was to compare serum midkine (S-MK) concentrations of GIST patients with those of healthy controls and to determine if MK can serve as a prognostic serum marker for these patients.
S-MK concentrations were measured by enzyme-linked immunosorbent assay in GIST patients (n = 96) and healthy controls (n = 148). S-MK levels were then correlated with clinicopathological data and the administration of imatinib therapy. In addition, MK expression was evaluated in 39 surgically resected GIST and in 17 leiomyoma specimens on a tissue microarray.
S-MK concentrations in GIST patients were significantly higher than in healthy controls: median (25th and 75th percentiles) S-MK concentration was 235 (139 and 376) pg/ml in the GIST patients and 99 (33 and 198) pg/ml in the controls (P < 0.001; Mann-Whitney U test). Significantly higher median S-MK concentrations were found in GIST with recurrence compared with those without (295 vs 230; P = 0.009). GIST patients with S-MK levels higher than 400 pg/ml showed a significantly worse recurrence-free survival (P = 0.026; log-rank test). Patients receiving imatinib therapy had decreased median S-MK concentrations compared with those who were not treated with imatinib (331 vs 201; P < 0.001).
S-MK concentration is a potential marker for evaluating the progression and prognosis of GIST, especially during imatinib therapy. Further studies could focus on the role of midkine in the tumorigenesis of GIST and responsiveness toward imatinib therapy.
Myeloid cells (granulocytes and monocytes/macrophages) play an important role in neuroblastoma. By inducing a complex immunosuppressive network, myeloid cells pose a challenge for the adaptive immune system to eliminate tumor cells, especially in high-risk neuroblastoma. This review first summarizes the pro- and anti-tumorigenic functions of myeloid cells, including granulocytes, monocytes, macrophages, and myeloid-derived suppressor cells (MDSC) during the development and progression of neuroblastoma. Secondly, we discuss how myeloid cells are engaged in the current treatment regimen and explore novel strategies to target these cells in neuroblastoma. These strategies include: (1) engaging myeloid cells as effector cells, (2) ablating myeloid cells or blocking the recruitment of myeloid cells to the tumor microenvironment and (3) reprogramming myeloid cells. Here we describe that despite their immunosuppressive traits, tumor-associated myeloid cells can still be engaged as effector cells, which is clear in anti-GD2 immunotherapy. However, their full potential is not yet reached, and myeloid cell engagement can be enhanced, for example by targeting the CD47/SIRPα axis. Though depletion of myeloid cells or blocking myeloid cell infiltration has been proven effective, this strategy also depletes possible effector cells for immunotherapy from the tumor microenvironment. Therefore, reprogramming of suppressive myeloid cells might be the optimal strategy, which reverses immunosuppressive traits, preserves myeloid cells as effectors of immunotherapy, and subsequently reactivates tumor-infiltrating T cells.
Activating mutations of anaplastic lymphoma kinase (ALK) have been identified as important players in neuroblastoma development. Our goal was to evaluate the significance of overall ALK activation in neuroblastoma. Expression of phosphorylated ALK, ALK, and its putative ligands, pleiotrophin and midkine, was screened in 289 neuroblastomas and 56 paired normal tissues. ALK was expressed in 99% of tumors and phosphorylated in 48% of cases. Pleiotrophin and midkine were expressed in 58% and 79% of tumors, respectively. ALK activation was significantly higher in tumors than in paired normal tissues, together with ALK and midkine expression. ALK phosphorylation and activation were largely independent of mutations and correlated with midkine expression in tumors. ALK activation in tumors was associated with favorable features, including a younger age at diagnosis, hyperdiploidy, and detection by mass screening. Antitumor activity of the ALK inhibitor TAE684 was evaluated in wild-type or mutated ALK neuroblastoma cell lines and xenografts. TAE684 was cytotoxic in vitro in all cell lines, especially those harboring an ALK mutation. TAE684 efficiently inhibited ALK phosphorylation in vivo in both F1174I and R1275Q xenografts but had antitumor activity only against the R1275Q xenograft. In conclusion, ALK activation occurs frequently during neuroblastoma oncogenesis, mainly through mutation-independent mechanisms. However, ALK activation is not associated with a poor outcome and is not always a driver of cell proliferation and/or survival in neuroblastoma.
Aims
Midkine (MK) is a multifunctional cytokine identified to be a promising cancer biomarker. Nuclear factor-kappa B (NF-κB) is an important transcription factor that plays a pivotal role in tumorigenesis. We aimed to investigate values of MK and NF-κB as markers for diagnosis and synchronous metastasis prediction in papillary thyroid cancer (PTC).
Main methods
76 cases of PTC and 70 cases of multi-nodular goiter (MNG) were retrieved. The PTC group was further divided into subgroup 1 (16 cases with synchronous metastases) and subgroup 2 (60 cases without metastases). A retrospective review of demographic and clinical information was performed. Immunohistochemistry of MK, NF-κB p65 and Ki-67 was performed on paraffin-embedded specimens and results were quantified. Diagnostic values of the parameters were conducted by receiver operating characteristic (ROC) curves. Protein levels of MK and NF-κB p65 were then confirmed by Western blot.
Key findings
Immunoreactivities of MK, NF-κB p65 and Ki-67 were significantly higher in the PTC group than in the MNG group with good differential diagnostic capabilities. Moreover, immunoreactivities of all three parameters were significantly higher in subgroup 1 than in subgroup 2 with good synchronous metastasis predictive efficacies. Western blot showed that MK and NF-κB p65 protein levels in lesions from subgroup 1 were significantly higher than those from subgroup 2, both of which were significantly higher than in MNG lesions.
Significance
We discovered that MK and NF-κB immunohistochemistries can potentially be used for differential diagnosis between PTC and MNG, and for prediction of synchronous metastases.
Midkine ( MK ) is a pleiotropic growth factor prominently expressed during embryogenesis but down‐regulated to neglible levels in healthy adults. Many published studies have demonstrated striking MK overexpression compared with healthy controls in various pathologies, including ischaemia, inflammation, autoimmunity and, most notably, in many cancers. MK expression is detectable in biopsies of diseased, but not healthy, tissues. Significantly, because it is a soluble cytokine, elevated MK is readily apparent in the blood and other body fluids such as urine and CSF , making MK a relatively convenient, accessible, non‐invasive and inexpensive biomarker for population screening and early disease detection. The first diagnostic tests that quantify MK are just now receiving regulatory clearance and entering the clinic. This review examines the current state of knowledge pertaining to MK as a biomarker and highlights promising indications and clinical settings where measuring MK could make a difference to patient treatment. I also raise outstanding questions about reported variants of MK as well as MK 's bio‐distribution in vivo . Answering these questions in future studies will enhance our understanding of the significance of measured MK levels in both patients and healthy subjects, and may reveal further opportunities for measuring MK to diagnose disease. MK has already proven to be a biomarker that can significantly improve detection, management and treatment of cancer, and there is significant promise for developing further MK ‐based diagnostics in the future.
Linked Article
This article is part of a recent themed section on Midkine, published in volume 171 issue 4. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐4
Background and objectives:
Midkine (MK) mRNA was highly expressed in various human cancer tissues and cells. The present study aimed to investigate whether MK mRNA level in peripheral blood mononuclear cells (PBMC) could serve as a diagnostic biomarker for patients having primary non-small cell lung cancer (NSCLC).
Methods:
MK mRNA level in PBMC from 87 patients with primary NSCLC, 35 patients with lung benign lesion (LEL), and 30 healthy volunteers was analyzed by real-time quantitative RT-PCR. The levels of serum carcinoembryonic antigen, carbohydrate antigen 125 (CA125), and neuron-specific enolase were detected by chemiluminescent microparticle enzyme immunoassay.
Results:
PBMC MK mRNA level was significantly higher in patients with primary NSCLC than that in other groups (P < 0.001), while there was no significant difference between LEL patients and healthy volunteers (P > 0.05). Higher MK mRNA level was correlated with clinical stages (P = 0.026), differentiation (P = 0.025), and lymph node metastasis (P = 0.022) of NSCLC. Using a cutoff of 0.0063, the sensitivity and specificity of MK mRNA levels to differentiate between patients with NSCLC and patients with LEL were 57.47 and 93.33 %,and it were 56.32 and 93.33 % for patients with NSCLC and healthy volunteers, respectively. Furthermore, multivariate analysis indicated that PBMC MK mRNA level above the cutoff value presented a chance of 11-fold higher for NSCLC occurrence.
Conclusions:
MK mRNA level in PBMC may be a potential non-invasive molecular marker for the diagnosis of primary NSCLC.
Cytokines released by cancer cells or by cells of the tumor microenvironment stimulate angiogenesis, act as autocrine or paracrine growth factors for malignant cells, promote tumor cell migration and metastasis or create an immunosuppressive microenvironment. These tumor-promoting effects of cytokines also apply to neuroblastoma (NB), a pediatric neuroectodermal malignancy with frequent metastatic presentation at diagnosis and poor prognosis. IL-6 and VEGF are the best characterized cytokines that stimulated tumor growth and metastasis, while others such as IFN-γ can exert anti-NB activity by inducing tumor cell apoptosis and inhibiting angiogenesis. On the other hand, cytokines are part of the anti-NB therapeutic armamentarium, as exemplified by IL-2 and granulocyte-macrophage colony stimulating factor that potentiate the activity of anti-NB antibodies. These recent results raise hope for more efficacious treatment of this ominous pediatric malignancy.
Purpose and Methods: Based on preliminary experience , there was a need for modifications and clarifications in the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Response Criteria (INRC). In 1988, a proposal was made to establish an internationally accepted staging system for neuro-blastoma, as well as consistent criteria for confirming the diagnosis and determining response to therapy (Brodeur GM, et al: J Clin Oncol 6:1874-1881, 1988). A meeting was held to review experience with the INSS and INRC and to revise or clarify the language and intent of the originally proposed criteria. Substantial changes included a redefinition of the midline, restrictions on age and bone marrow involvement for stage 45, and the recommendation that meta-iodobenzylguanidine (MIBG) scanning be implemented for evaluating the extent of disease. Other modifications and clarifications of the INSS and INRC are presented. In addition, the criteria for the diagnosis of neuroblastoma were modified. Finally , proposals were made for the development of risk groups that incorporate both clinical and biologic features in the prediction of prognosis. The biologic features that were deemed important to evaluate prospectively included serum ferritin, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH); tumor histology; tumor-cell DNA content; assessment of N-myc copy number; assessment of lp deletion by cytogenetic or molecular methods; and TRK-A expression. Results and Conclusion: Modifications of the INSS and INRC made at this conference are presented. In addition, proposals are made for future modifications in these criteria and for the development of International Neuro-blastoma Risk Groups.
Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival.
All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months.
The mean (+/-SE) event-free survival rate three years after the first randomization was significantly better among the 189 patients who were assigned to undergo transplantation than among the 190 patients assigned to receive continuation chemotherapy (34+/-4 percent vs. 22+/-4 percent, P=0.034). The event-free survival rate three years after the second randomization was significantly better among the 130 patients who were assigned to receive 13-cis-retinoic acid than among the 128 patients assigned to receive no further therapy (46+/-6 percent vs. 29+/-5 percent, P=0.027).
Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma. In addition, treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.
Pleiotrophin (PTN) and midkine (MK) are members of a new family of neurotrophic factors whose expression is developmentally regulated. PTN also transforms NIH 3T3 cells, and MK is mitogenic to certain cell lines. Neuroblastomas are tumors derived from neural crest cells, and recent studies have revealed that the biology of these tumors is at least partly regulated by neurotrophic factors and their receptors. To examine the expression of PTN and MK in neuroblastoma, we analyzed their mRNA expression in 72 primary neuroblastomas and 11 neuroblastoma cell lines as well as other tissues and cell lines. PTN is highly expressed in favorable neuroblastomas (stages I, II, and IV-S, n = 44), whereas it is expressed at a significantly lower level in advanced tumors (stages III and IV, n = 28, P = 0.003). PTN is not expressed in either aggressive neuroblastomas with N-myc amplification or in neuroblastoma cell lines. Moreover, the expression pattern of PTN was similar to that of TRK-A, the high affinity receptor for nerve growth factor, in that it is correlated with a favorable prognosis (P < 0.004). In contrast, MK is highly expressed in almost all primary neuroblastomas and cell lines and showed no correlation with disease stage or N-myc amplification. These results suggest that differential expression of PTN and MK may have an important role in regulating growth and differentiation of neuroblastomas.
PURPOSE AND METHODS: Based on preliminary experience, there was a need for modifications and clarifications in the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Response Criteria (INRC). In 1988, a proposal was made to establish an internationally accepted staging system for neuroblastoma, as well as consistent criteria for confirming the diagnosis and determining response to therapy (Brodeur GM, et al: J Clin Oncol 6:1874-1881, 1988). A meeting was held to review experience with the INSS and INRC and to revise or clarify the language and intent of the originally proposed criteria. Substantial changes included a redefinition of the midline, restrictions on age and bone marrow involvement for stage 4S, and the recommendation that meta-iodobenzylguanidine (MIBG) scanning be implemented for evaluating the extent of disease. Other modifications and clarifications of the INSS and INRC are presented. In addition, the criteria for the diagnosis of neuroblastoma were modified. Finally, proposals were made for the development of risk groups that incorporate both clinical and biologic features in the prediction of prognosis. The biologic features that were deemed important to evaluate prospectively included serum ferritin, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH); tumor histology; tumor-cell DNA content; assessment of N-myc copy number; assessment of 1p deletion by cytogenetic or molecular methods; and TRK-A expression. RESULTS AND CONCLUSION: Modifications of the INSS and INRC made at this conference are presented. In addition, proposals are made for future modifications in these criteria and for the development of International Neuroblastoma Risk Groups.
Midkine (MK) is a growth factor identified as a product of a retinoic acid-responsive gene. A truncated form of MK mRNA, which lacks a sequence encoding the N-terminally located domain, was recently found in cancer cells. We investigated the expression of the truncated MK mRNA in specimens of 47 surgically removed human gastrointestinal organs using polymerase chain reaction. Truncated MK was not detected in all of the 46 corresponding non-cancerous regions. On the other hand, this short MK mRNA was expressed in the primary tumours in 12 of 16 gastric cancers, 8 of 13 colorectal carcinomas, five of nine hepatocellular carcinomas, two of two oesophageal carcinomas and one ampullary duodenal cancer. In addition, truncated MK was detectable in all of the 14 lymph node metastases but in none of three metastatic sites in the liver, suggesting that truncated MK mRNA could become a good marker of nodal metastases in gastrointestinal tract.
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It has been suggested that a heparin-binding growth factor, midkine (MK), plays an important role in carcinogenesis because of its frequent overexpression in various malignant tumours. To clarify whether or not MK contributes to the early stage of carcinogenesis, we examined the status of MK mRNA in 20 adenomas with moderate- and severe-grade dysplasia, 28 carcinomas and 28 corresponding normal tissues, by means of Northern blotting. The MK expression level was significantly more elevated in adenomas than in normal tissues (P < 0.001, unpaired Student's t-test). A difference was also observed between carcinomas and the corresponding normal tissues (P < 0.04, paired Student's t-test). Moreover, MK immunostaining was positive in the adenomas with moderate- and severe-grade dysplasia and in the carcinomas, but not in mild-grade dysplasia or in normal tissues. These findings were in line with those on Western blotting. In three patients with both adenomas with moderate- or severe-grade dysplasia and carcinomas, elevated MK expression was observed in the neoplastic lesions. This is the first report of the association of elevated MK expression with the early stage of carcinogenesis in humans.
The treatment of advanced neuroblastoma (NB) or Ewing's sarcoma (ES) is one of the major challenges in pediatric oncology. Both malignancies are refractory to conventional therapies and have an extremely poor prognosis. High-dose myeloablative radiochemotherapy with autologous bone marrow or peripheral blood stem cell rescue is one of the most aggressive treatments attempted for these diseases but is often undermined by residual tumor cells contaminating the graft. Thus, in this approach, purging of tumor cells from the graft is key to the prevention of relapse after transplantation. We investigated a novel approach to eliminate tumor cells from the bone marrow or peripheral blood stem cell graft without causing stem cell damage through the use of a conditionally replicative adenovirus (Ad). ES and NB are sensitive to Ad infection, and advanced NBs express a high level of the growth/differentiation factor midkine (MK). We confirmed in this study that ES cell lines (SK-ES-1 and RD-ES) are also sensitive to Ad infection and express high levels of MK. In contrast, CD34+ stem cells are refractory to Ad infection and express very little MK. A conditionally replicative Ad in which the expression of E1 is controlled by the MK promoter achieved good levels of viral replication in NB or ES and induced remarkable tumor cell killing. On the other hand, this virus caused no damage to CD34+ cells even after 3 h of infection at a dose of 1000 multiplicity of infection. We concluded that application of this replication-competent Ad to hematopoietic grafts could be a simple but effective procedure to achieve complete tumor cell purging.
The heparin-binding growth factor midkine (MK) is the product of a retinoic acid-responsive gene, and is implicated in neuronal survival and differentiation, and carcinogenesis. We previously reported that MK mRNA expression is elevated in neuroblastoma specimens at all stages, whereas pleiotrophin, the other member of the MK family, is expressed at high levels in favourable neuroblastomas. As MK is a secretory protein, it can be detected in the blood. Here, we show a significant correlation of the plasma MK level with prognostic factors of neuroblastomas. The plasma MK level was determined in 220 patients with neuroblastomas, and compared with that in children without malignant tumors (n=17, <500 pg ml(-1)). The plasma MK level became significantly elevated with advancing stages (stage 1: 445 pg ml(-1) (median), n=73; stage 2: 589, n=39; stage 3: 864, n=40; stage 4: 1445, n=56; and stage 4S: 2439, n=12). More importantly, a higher MK level was strongly correlated with poor prognostic factors: over 1 year of age (P=0.0299), MYCN amplification (P<0.0001), low TrkA expression (P=0.0005), nonmass screening, sporadic neuroblastomas (P<0.0001), and diploidy/tetraploidy (P=0.0007). Thus, these results demonstrate that the plasma MK level is a good marker for evaluating the progression of neuroblastomas. Moreover, considering the ability of antisense MK oligodeoxyribonucleotide to suppress tumour growth of colorectal carcinoma cells in nude mice, as recently reported, the present study suggests that MK is a possible candidate molecular target for therapy for neuroblastomas.
The International Neuroblastoma Pathology Committee, which is comprised of six member pathologists, was convened with the objective of proposing a prognostically significant and biologically relevant classification based on morphologic features of neuroblastic tumors (NTs) (i.e., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma).
Cases of spontaneous regression of neuroblastoma continue to occur in the present multimodal therapy era at institutions where physicians are prepared to withhold treatment on certain patients with residual primary or metastatic disease. From a survey of the 22 member institutions of Children's Cancer Study Group, seven hospitals submitted data on 24 neuroblastoma patients whose disease underwent regression after minimal, unusual, or no treatment. An analysis of these patients and of 33 patients from two large series in the literature shows that the majority of patients are infants with Stage II or Stage IVS disease. The spontaneous regression usually consists of complete disappearance of the disease, but in some neuroblastomas, maturation to ganglioneuroma takes place. The various factors that may influence regression are discussed.
Learning Objectives
After completing this course, the reader will be able to:
Appreciate the heterogeneity of neuroblastoma and identify clinical and biological prognostic factors. Explain the determinants and the clinical significance of the neuroblastoma risk stratification system. Select appropriate treatment regimens for neuroblastoma patients that are tailored according to risk stratification.
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Neuroblastoma, a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behavior ranging from spontaneous remission to rapid tumor progression and death. To a large extent, outcome can be predicted by the stage of disease and the age at diagnosis. However, the molecular events responsible for the variability in response to treatment and the rate of tumor growth remain largely unknown. Over the past decade, transformation-linked genetic changes have been identified in neuroblastoma tumors that have contributed to the understanding of tumor predisposition, metastasis, treatment responsiveness, and prognosis. The Children's Oncology Group recently developed a Neuroblastoma Risk Stratification System that is currently in use for treatment stratification purposes, based on clinical and biologic factors that are strongly predictive of outcome. This review discusses the current risk-based treatment approaches for children with neuroblastoma and recent advances in biologic therapy.
Known prognostic factors in neuroblastoma were analyzed in 124 children to determine which were independent and which were most useful in predicting outcome. The following factors were analyzed: age, sex, stage of disease, serum neuron-specific enolase (NSE), serum ferritin, E-rosette inhibition, urinary catecholamines, and histologic type according to the criteria of Shimada. Estimates of survival were calculated using the method of Kaplan and Meier. The overall survival for 124 patients was 60% at 2 years. There were significant differences in survival by pathology, age, NSE, ferritin, vanilmandelic acid (VMA): homovanillic acid (HVA) ratio, and stage. There was a strong association among NSE, age, stage, and ferritin. Using the recursive partitioning approach, it was possible to subdivide patients into three groups (based on diagnostic values of ferritin, age, and stage) with a good, intermediate, and poor prognosis and estimated 2-year survival of 100%, 62%, and 19%, respectively. Further analysis could not be done because of small numbers in the subgroups, but the results suggest that combinations of age, stage, serum ferritin, and histologic type may be able to define two populations: favorable with 80% + 2-year survival and unfavorable with less than 20%.
BACKGROUND
The International Neuroblastoma Pathology Committee, which is comprised of six member pathologists, was convened with the objective of proposing a prognostically significant and biologically relevant classification based on morphologic features of neuroblastic tumors (NTs) (i.e., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma).METHODSA total of 227 cases were reviewed. Consensus diagnoses from morphologic features (criteria described separately) based on five of six or six of six agreements by the reviewer pathologists were used for prognostic analysis. Prognostic effects of morphology, both individual and in combination, taken in conjunction with age (Shimada classification, histologic grade, and risk group), were analyzed.RESULTSApproximately 99% of cases (224 of 227) had consensus diagnoses for categorization: neuroblastoma (Schwannian stroma-poor), 190 cases; ganglioneuroblastoma, intermixed (Schwannian stroma-rich), 5 cases; ganglioneuroma (Schwannian stroma-dominant) maturing, 1 case; ganglioneuroblastoma, nodular (composite Schwannian stroma-rich/stroma-dominant and stroma-poor), 19 cases; and NT-unclassifiable, 9 cases. For the NTs, subtype (93% consensus: undifferentiated, 6 cases; poorly differentiated, 155 cases; and differentiated, 15 cases), mitosis-karyorrhexis index (90% consensus: low, 94 cases; intermediate, 40 cases; and high, 37 cases), mitotic rate (75% consensus: low, 89 cases; high, 50 cases; and not determined, 4 cases), and calcification (100% consensus: yes, 110 cases and no, 80 cases) were recorded. Statistical analysis demonstrated that the Shimada classification system (90% consensus; 3-year event free survival: 85% for the group with favorable histology and 41% for the group with unfavorable histology; P = 0.31 × 10−9) had a significantly stronger prognostic effect than individual features and other combinations.CONCLUSIONS
The International Neuroblastoma Pathology Classification, a system based on a framework of the Shimada classification with minor modifications, is proposed for international use in assessing NTs. Cancer 1999;86:364–72. © 1999 American Cancer Society.
Case of spontaneous regression of neuroblastoma continue to occur in the present multimodal therapy era at institutions where physicians are prepared to withhold treatment on certain patients with residual primary or metastatic disease. From a survey of the 22 member institutions of Children's Cancer Study Group, seven hospitals submitted data on 24 neuroblastoma patients whose disease underwent regression after minimal, unusual, or no treatment. An analysis of these patients and of 33 patients form two large series in the literature shows that the majority of patients are infants with Stage II or Stage IVS disease. The spontaneous regression usually consists of complete disappearance of the disease, but in some neuroblastomas, maturation to ganglioneuroma takes place. The various factors that may influence regression are discussed.
Spontaneous maturation of Stage IVS neuroblastoma has been postulated as a mechanism for its favorable prognosis, but this has rarely been documented pathologically. We report on a patient with congenital Stage IVS neuroblastoma who had extensive subcutaneous and bone-marrow involvement. Serial photographs, biopsies, and vanillomandelic acid determinations documented the tumor's initial progression which was followed by spontaneous maturation and involution of the patient's disease over a 6-year period. No cytotoxic therapy was administered. Favorable biologic prognostic factors were documented, including tumor DNA and protein analyses for N-myc amplification or overexpression and analysis for serum neuron-specific enolase and ferritin. Implications for management and therapy of Stage IVS neuroblastoma are discussed with reference to this case and the recent literature.
Midkine (MK) is a heparin-binding growth factor specified by a retinoic acid responsive gene. A rabbit was immunized against recombinant MK produced in L cells, and the resulting antibody was affinity purified using MK-glutathione S-transferase fusion protein as a ligand. The MK-specific antibody was used to investigate the function and distribution of MK. MK of the same size as the recombinant MK produced in L cells (13 kDa) was strongly detected in a 13-day rat embryo. Weak expression was observed in the brains of a 19-day embryo, neonates, and adults. In the 13-day mouse embryos, high levels of MK were detected on the surfaces of brain cells, as well as in basement membranes and in the epithelial cells of the intestine, the jaw, and the rib. Nerve cells from the brains of 13-day or 19-day rat embryos extended neurites about twofold more efficiently on MK-coated dishes than on poly-L-lysine-coated dishes. Furthermore, anti-MK antibody inhibited neurite extension not only on MK-coated dishes, but also on poly-L-lysine-coated dishes. These results suggest that MK is an endogenous neurite outgrowth factor involved in the development of the central nervous system. Anti-MK antibody was also found to inhibit growth of Wilms' tumor cells, which secreted MK into culture medium. Thus, overproduction of MK is involved in enhanced growth of Wilms' tumor cells.
Neuroblastoma, a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behavior, ranging from spontaneous remission to rapid tumor progression and death. To some extent, outcome can be predicted by the stage of disease and age at diagnosis. The molecular events responsible for the variability in response to treatment and rate of tumor growth, however, remain largely unknown. Over the past decade, transformation-linked genetic changes have been identified in neuroblastoma tumors that have contributed to our understanding of tumor predisposition, metastasis, treatment responsiveness, and prognosis. This review discusses the recent advances in the understanding of neuroblastoma at the cellular and molecular levels, and the role that tumor biology plays in determining appropriate risk-based treatment for patients with neuroblastoma.
The process of metastasis consists of a series of linked, sequential steps. Although some of the steps in this process contain stochastic elements, metastasis as a whole favors the survival and growth of a few subpopulations of cells that preexist within the parent neoplasm. Metastases can have a clonal origin, and different metastases can originate from the proliferation of single cells. The outcome of metastasis depends on the interaction of metastatic cells with various host factors. Organ-specific metastases have been demonstrated in a variety of tumors and may even be specific to a particular site within one organ. Studies from our laboratory and from others have shown that the implantation of human cancer cells derived from surgical specimens into correct anatomic sites of nude mice provides a suitable model of metastasis of human tumors. Clonal analysis of human melanomas revealed that these tumors are heterogeneous for metastatic properties and that growth in the environment of specific organs is selective. These data suggest that systemic physiologic signals can be recognized by neoplastic cells, presumably by mechanisms similar to those shared by their normal cell counterparts. Elucidation of the mechanisms that regulate metastasis should lead to better therapeutic interventions.
The International Neuroblastoma Pathology Committee, which is comprised of six member pathologists, was convened with the objective of proposing a prognostically significant and biologically relevant classification based on morphologic features of neuroblastic tumors (NTs) (i.e., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma).
A total of 227 cases were reviewed. Consensus diagnoses from morphologic features (criteria described separately) based on five of six or six of six agreements by the reviewer pathologists were used for prognostic analysis. Prognostic effects of morphology, both individual and in combination, taken in conjunction with age (Shimada classification, histologic grade, and risk group), were analyzed.
Approximately 99% of cases (224 of 227) had consensus diagnoses for categorization: neuroblastoma (Schwannian stroma-poor), 190 cases; ganglioneuroblastoma, intermixed (Schwannian stroma-rich), 5 cases; ganglioneuroma (Schwannian stroma-dominant) maturing, 1 case; ganglioneuroblastoma, nodular (composite Schwannian stroma-rich/stroma-dominant and stroma-poor), 19 cases; and NT-unclassifiable, 9 cases. For the NTs, subtype (93% consensus: undifferentiated, 6 cases; poorly differentiated, 155 cases; and differentiated, 15 cases), mitosis-karyorrhexis index (90% consensus: low, 94 cases; intermediate, 40 cases; and high, 37 cases), mitotic rate (75% consensus: low, 89 cases; high, 50 cases; and not determined, 4 cases), and calcification (100% consensus: yes, 110 cases and no, 80 cases) were recorded. Statistical analysis demonstrated that the Shimada classification system (90% consensus; 3-year event free survival: 85% for the group with favorable histology and 41% for the group with unfavorable histology; P = 0.31 x 10(-9)) had a significantly stronger prognostic effect than individual features and other combinations.
The International Neuroblastoma Pathology Classification, a system based on a framework of the Shimada classification with minor modifications, is proposed for international use in assessing NTs.
Midkine (MK) is a new member of the heparin-binding neurotrophic factor family. MK plays important roles in development and carcinogenesis and has several important biological effects, including promotion of neurite extension and neuronal survival. However, the mechanism by which MK exerts its neurotrophic actions on neurons has not been elucidated to date. We have established an apoptosis induction system by serum deprivation in primary neuronal cultures isolated from mouse cerebral cortices. Neuronal apoptosis induced by serum deprivation was accompanied by the activation of caspase-3. MK, when added into the culture medium, inhibited the induction of apoptosis and activation of caspase-3 in a dose-dependent manner. Extracellular signal-regulated kinase (ERK) and Akt were not activated by serum deprivation, whereas ERK and Akt were rapidly activated by addition of MK. In addition, the trophic actions of MK of suppressing apoptosis and suppressing the activation of caspase-3 were abolished by concomitant treatment with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase, and with wort-mannin or LY294002, specific inhibitors of phosphatidyl-inositol 3-kinase (PI 3-kinase). These PI 3-kinase inhibitors also inhibited the activation of ERK in response to MK, demonstrating a link between ERK and the caspase-3 pathway that is modulated by the PI 3-kinase activation. These results indicate that the ERK cascade plays a central role in MK-mediated neuronal survival via inhibition of caspase-3 activation.
The major cause of death from cancer is due to metastases that are resistant to conventional therapies. Several reasons account for the failure to treat metastases. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, the process of metastasis selects for a small subpopulation of cells that preexist within a parental neoplasm. Third, and perhaps the greatest obstacle for therapy, is that the outcome of metastasis depends on multiple interactions ('cross-talk') of metastatic cells with homeostatic mechanisms which the tumor cells usurp. Most recent data demonstrate that the organ microenvironment can influence the growth, invasion, and response of metastases to chemotherapy. Therapy of metastasis should therefore be targeted against both the metastatic tumor cells and the homeostatic factors that promote metastasis.
Midkine (MK) and pleiotrophin (PTN) are low molecular weight proteins with closely related structures. They are mainly composed of two domains held by disulfide bridges, and there are three antiparallel beta-sheets in each domain. MK and PTN promote the growth, survival, and migration of various cells, and play roles in neurogenesis and epithelial mesenchymal interactions during organogenesis. A chondroitin sulfate proteoglycan, protein-tyrosine phosphatase zeta (PTPzeta), is a receptor for MK and PTN. The downstream signaling system includes ERK and PI3 kinase. MK binds to the chondroitin sulfate portion of PTPzeta with high affinity. Among the various chondroitin sulfate structures, the E unit, which has 4,6-disulfated N-acetylgalactosamine, provides the strongest binding site. The expression of MK and PTN is increased in various human tumors, making them promising as tumor markers and as targets for tumor therapy. MK and PTN expression also increases upon ischemic injury. MK enhances the migration of inflammatory cells, and is involved in neointima formation and renal injury following ischemia. MK is also interesting from the viewpoints of the treatment of neurodegenerative diseases, increasing the efficiency of in vitro development, and the prevention of HIV infection.
Midkine, a heparin-binding growth factor, is expressed in numerous cancer tissues and is reportedly elevated in patients with various neoplasms. The aim of this study was to evaluate the clinicopathological significance of serum midkine concentration (S-MK) in patients with superficial esophageal squamous cell carcinoma (SCC). Pretreatment S-MK was measured by enzyme-linked immunosorbent assay in 135 healthy controls, 16 patients with benign esophageal disease, and 60 patients with primary superficial esophageal squamous cell cancer (SESCC). All patients with SESCC underwent curative resection. The disease was staged according to TNM/UICC guidelines. Serum concentrations of carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag), and cytokeratin 19 fragment (CYFRA21-1) were also evaluated in the same populations. S-MK in patients with SESCC (388+/-411 pg/ml) was significantly higher than in benign esophageal disease or healthy controls (183+/-73 and 154+/-76 pg/ml, respectively). Using the mean + 2 standard deviations of healthy control S-MK (300 pg/ml) as the cut-off level, 50% of patients with esophageal SESCC were deemed positive. This S-MK positivity rate for detecting SESCC was significantly higher than for other tumor markers. Thus, S-MK may be useful as a tumor marker to detect SESCC.
Neuroblastoma, a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behavior ranging from spontaneous remission to rapid tumor progression and death. To a large extent, outcome can be predicted by the stage of disease and the age at diagnosis. However, the molecular events responsible for the variability in response to treatment and the rate of tumor growth remain largely unknown. Over the past decade, transformation-linked genetic changes have been identified in neuroblastoma tumors that have contributed to the understanding of tumor predisposition, metastasis, treatment responsiveness, and prognosis. The Children's Oncology Group recently developed a Neuroblastoma Risk Stratification System that is currently in use for treatment stratification purposes, based on clinical and biologic factors that are strongly predictive of outcome. This review discusses the current risk-based treatment approaches for children with neuroblastoma and recent advances in biologic therapy.
The aim of this study was to conduct a systematic review, and where possible meta-analyses, of molecular and biological tumor markers described in neuroblastoma, and to establish an evidence-based perspective on their clinical value for the screening, diagnosis, prognosis, and monitoring of patients. Experimental Design: A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000.
A total of 428 papers studying the use of 195 different tumor markers in neuroblastoma were identified. Small sample sizes, poor statistical reporting, large heterogeneity across studies (e.g., in cutoff levels), and publication bias limited meta-analysis to the area of prognosis only; MYCN, chromosome 1p, DNA index, vanillylmandelic acid:homovanillic acid ratio, CD44, Trk-A, neuron-specific enolase, lactate dehydrogenase, ferritin, and multidrug resistance were all identified as potentially important prognostic tools.
This systematic review forms a knowledge base of the tumor markers studied thus far in neuroblastoma, and has identified some of the most important prognostic markers, which should be considered in future research and treatment strategies. Importantly, the review has also highlighted some general problems across primary tumor marker studies, in particular poor and heterogeneous reporting. These need to be addressed to allow better clinical interpretation and enable more appropriate evidence-based reviews in the future. In particular, collaboration of cancer research groups is needed to enable bigger sample sizes, standardize methods of analysis and reporting, and facilitate the pooling of individual patient data.
The midkine (MK) family consists of only two members, namely heparin-binding growth factors MK and pleiotrophin (PTN). During embryogenesis, MK is highly expressed in the mid-gestational period, whereas PTN expression reaches the maximum level around birth. Both proteins are localized in the radial glial processes of the embryonic brain, along which neural stem cells migrate and differentiate. Zebrafish and Xenopus MK can induce neural tissues. In addition, deposits of MK and/or PTN are found in neurodegenerative diseases, such as Alzheimer's disease and multiple system atrophy. Both molecules are induced in reactive astrocytes by ischemic insults. In this context, it is interesting that LDL receptor-related protein is a receptor for MK and PTN, and this receptor has been implicated in the pathogenesis of Alzheimer's disease. MK and PTN share receptors, and show similar biological activities that include fibrinolytic, anti-apoptotic, mitogenic, transforming, angiogenic, and chemotactic ones. These activities explain how these molecules are involved in carcinogenesis. MK is detected in human carcinoma specimens from pre-cancerous stages to advanced stages. Strong expression of PTN is also detected in several carcinomas, although, in general, MK is expressed more intensely and in a wide range of carcinomas than PTN. The blood MK level is frequently elevated in advanced human carcinomas, decreases after surgical removal of the tumors, and is correlated with prognostic factors. Thus, it is a good market for evaluating the progress of carcinomas. Furthermore, antisense oligonucleotides for MK and ribozymes for PTN show anti-tumor activity. Therefore, MK and PTN are candidate molecular targets for therapy for human carcinomas.
Midkine (MK) is one of a family of heparin-binding growth factors, and increased MK expression is reported in various types of human carcinomas. To clarify the association between serum MK (S-MK) concentrations and gastric cancer, we examined S-MK concentrations of gastric cancer patients (n=275) and healthy controls (n=275). S-MK concentrations of all subjects were measured by enzyme-linked immunosorbent assay (elisa). The medians (25th and 75th percentiles) of S-MK were 192 (123 and 314) pg/mL in the cases and 170 (81 and 273) pg/mL in the controls (P <0.01). We also compared S-MK concentrations in each group divided by the progression stage or histological type of cancer. A difference was observed in the median S-MK concentrations between early and advanced cancers [182 (105 and 301) pg/mL vs 203 (139 and 331) pg/mL, P=0.07], but not between intestinal and diffuse type cancers [185 (121 and 306) pg/mL vs 198 (127 and 323) pg/mL, P=0.51]. We found that those progression stages affect S-MK concentration more strongly than the histological types in gastric cancer patients. Because S-MK seems to reflect the progression stage of gastric cancer, it may serve as a useful marker in the clinical follow-up of gastric cancer patients.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue tumors arising sporadically although more frequently in patients with Neurofibromatosis type 1. Prognosis remains dismal as chemo- and radiotherapy have not been shown to be successful. The heparin-binding growth factor, Midkine (MK), is implicated in the tumorigenesis of benign and plexiform neurofibromas, and thereof arising MPNSTs. MK is mitogenic, anti-apoptotic, angiogenic and can promote tumorigenicity in several cell types. Thus, we investigated the role of MK in malignant biology and tumorigenicity in MPNSTs by stable transfection into MPNST cell lines. Overexpression of MK in the MPNST cell line, S462, increased cell viability and protected cells from apoptosis under serum deprivation, but did not induce proliferation. In addition, MK-transfected S462 cells were partially protected from vincristine-induced cell death. Conditioned medium of MK-transfected S462 cells was a potent mitogen for human umbilical venous endothelial cells. Furthermore, MK overexpression in S462 cells was accompanied by higher levels of VEGF mRNA. Yet, stable overexpression of MK in S462 as well as in ST88-14 cells was not sufficient to promote xenograft tumor growth in nude mice. However, increasing survival and enhanced angiogenic potency of MK-transfected S462 cells highlight the importance of developing specific inhibitors for MK as part of new therapeutic concepts against MPNSTs.
Germany e-mail: henning.fiegel@medizin.uni-leipzig Izbicki Department of General Surgery
- H C Fiegel
- R Wachowiak
- R Metzger
- D Kluth Á Hde
- J T Kaifi
H. C. Fiegel (&) Á R. Wachowiak Á R. Metzger Á D. Kluth Á H. Till Department of Pediatric Surgery, University of Leipzig, Liebigstrasse 20 A, 04103 Leipzig, Germany e-mail: henning.fiegel@medizin.uni-leipzig.de J. T. Kaifi Á J. R. Izbicki Department of General Surgery, Universitä Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany A. Quaas Department of Pathology, Universitä Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany K. Aridome Department of Surgery, Kagoshima University, Kagoshima, Japan K. Ichihara-Tanaka Á T. Muramatsu Department of Health Science, Faculty of Psychological and Physical Sciences, Aichi Gakuin University, Aichi, Japan R. Erttmann Department of Pediatric Hematology/Oncology, Universitä Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany 123 Pediatr Surg Int (2008) 24:1355–1359 DOI 10.1007/s00383-008-2263-0 References
Midkine and pleiotropin in neural development and cancer
- K Kadomatsu
- Muramatsu
Kadomatsu K, Muramatsu T (2004) Midkine and pleiotropin in neural development and cancer. Cancer Lett 204:127–143
Prognostic factors in neuroblastoma
- A E Evans
- D Angio
- G J Propert
- K Anderson
- J Hann
- AE Evans