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Original article

Possible impact of NCAM and FGFR1 molecule expression patterns on the biological behavior of renal cell carcinoma

Isidora Filipović1,2, Ana Mioljević2, Gorana Nikolić1,2, Jelena Filipović1,2, Sanja Radojević Škodrić1,2, Nikola Bogosavljević2,3, Maja Životić1,2
  • University of Belgrade, Faculty of Medicine, Institute of Pathology, Belgrade, Serbia
  • University of Belgrade, Faculty of Medicine, Belgrade, Serbia
  • Institute of orthopedics “Banjica”, Belgrade, Serbia

ABSTRACT

Introduction: The incidence of renal cell tumors (RCT) and the deaths caused by them has been increasing in recent decades. Although renal cell carcinomas (RCCs) represent only 2% of all cancers, these tumors are among the top ten causes of death in Europe, when cancers are concerned.

Aim: As it is known that the neural cell adhesion molecule (NCAM) and fibroblast growth factor receptor 1 (FGFR1) interact on the surface of the cell membrane and can also be expressed in other cellular localizations, we decided to examine the potential influence of different patterns of their co-expression on the clinical and pathological characteristics of renal tumors.

Material and methods: A total of 100 renal tumors, diagnosed at the Institute of Pathology, Faculty of Medicine, University of Belgrade, were analyzed. Immunohistochemical analysis was performed on tissue microarray slides, using NCAM (1:50, clone123C3.D5) and FGFR1 (1:100, clone M19B2) antibodies. Clinical and pathohistological characteristics of renal tumors were examined in relation to the presence and localization of the co-expression of NCAM and FGFR1 molecules.

Results: Co-expression of NCAM and FGFR1 molecules in renal tumors was observed in the cytoplasm and on the membrane, however, these patterns did not depend on the pathohistological type of tumor. Each tumor in which FGFR1 immunopositivity was observed in the nucleus also showed membranous positivity for both tested molecules. It was observed that the frequency of co-expression of NCAM and FGFR1 molecules increased with increasing T stage, but the finding was not statistically significant.

Conclusion: Membranous co-expression was not observed in any benign tumor, despite the presence of cytoplasmic co-expression. There is also a possibility that the presence of FGFR in the nucleus induces the occurrence of membranous co-expression.


INTRODUCTION

Over the past three decades, the incidence of renal tumors has been steadily increasing in Europe, USA, and Australia [1],[2]. In the adult population, kidney cancers account for 2% of all cancers [3], with the most common one being renal cell carcinoma (RCC), which has the highest mortality among urogenital system cancers [4]. There are several pathohistological subtypes, among which there are differences in morphology, genetics, origin, and biological behavior. Clear cell carcinoma is by far the most common (80% – 90%) type, followed by papillary, chromophobe, and collecting duct carcinoma [5]. Although the most common renal cell tumors are carcinomas, there are also benign tumors known as oncocytomas [6]. About 270,000 new cases of RCC are diagnosed annually worldwide, and about 116,000 patients die [1],[2]. Given the fact that these tumors rarely show early signs of disease (resulting in a high proportion of patients with metastases), as well as the fact that they are characterized by diverse clinical manifestations and increased resistance to radiotherapy and chemotherapy [7], many clinical and pathological examinations have been conducted for the purpose of discovering potential biomarkers and enabling early diagnosis and immunomodulation with the aim of inhibiting tumor growth.

Neural cell adhesion molecule (NCAM) is a transmembrane protein expressed in many tissues during organogenesis. It plays a significant role during embryonic development, not only in nerve, muscle, neuroectodermal and neuroendocrine tissue, but also in organs of different origin, including kidneys, with an important role in the process of mesenchymal-epithelial transformation (MET), migration and proliferation [8]. In the adult kidney, NCAM is present only in rare interstitial cells [9], as well as in renal neoplasms [10].

The fibroblast growth factor receptor (FGFR) belongs to the family of tyrosine-kinase receptors, important for cell proliferation and migration, differentiation, apoptosis, epithelial-mesenchymal transition (EMT) and carcinogenesis [11],[12],[13],[14]. FGFR receptors can also be activated by some transmembrane molecules, including NCAM [15]. The interactions between these two molecules have been described in nervous [16] and non-nervous tissue [17], but also in tumors [18].

Apart from data supporting the fact that each of these two molecules participates in the processes of migration, proliferation, as well as processes of epithelial-mesenchymal transition (EMT), leading to the transformation of a normal epithelial cell into a neoplastic cell with mesenchymal characteristics, there are also data on their interaction as a factor enhancing the invasive potential of certain carcinoma [19]. The interaction between NCAM and FGFR molecules, their expression in proliferating tumor cells and metastases of various tumors, but also the described expression in renal neoplasms, makes these molecu

les, as surface markers, suitable for establishing a diagnosis, but also makes them a potential target for the application of new therapeutic modalities [20],[21],[22],[23],[24],[25],[26],[27],[28].

As NCAM and FGFR are known to interact on the surface of the cell membrane, we decided to investigate the potential impact of different patterns of their co-expression on the clinicopathological characteristics of renal cell tumors.

MATERIALS AND METHODS

Tissue samples for analysis and tissue microarray

Sample cylinders of tissue were taken from paraffin molds of renal tumor tissue, diagnosed in the period 2010 – 2013 at the Institute of Pathology of the Faculty of Medicine, University of Belgrade, for making a tissue microarray. Sampling was performed from paraffin molds of renal cell tumors with a hollow needle (0.6 mm in diameter). Three tissue cylinders were taken from each mold, which were then embedded in a paraffin block and precisely arranged in an array. Using a microtome, tissue microarray paraffin molds were cut into 5 μm thick sections and mounted on microscope slides, which were further used for immunohistochemical analysis.

Tumor tissue samples were obtained from 100 renal tumors, among which there were 69 clear cell RCCs, 12 papillary RCCs, 7 chromophobe RCCs, 5 multilocular cystic RCCs, two Bellini duct carcinomas, and 5 oncocytomas.

Immunohistochemistry

Immunohistochemistry was performed on tissue microarray slides. After deparaffinization in xylene and hydration, the slides were placed in a citrate buffer (pH 6.0) and exposed to microwaves for 20 min, at 400 W. Peroxidase activity was blocked with 1% bovine serum albumin (BSA). After antigen extraction, incubation with primary NCAM antibodies (1:50, clone 123C3.D5, LabVision, USA) and FGFR1 (1:100, clone M19B2, Abcam, USA) was performed for one hour. EnVisionTM (DAKO, Denmark) was used to visualize the antigen-antibody reaction with 3,3’-diaminobenzidine (DAB) and subsequent contrast with hemalaun (Mertz, USA). Negative controls were obtained by excluding the primary antibody. Plates were examined using a BX53 light microscope with a DP12CCD camera (Olympus, Germany).

Statistical analysis

Statistical analysis was performed using IBM SPSS software, version 20.0. The χ2 test, Fisher’s test, Student’s t test, Mann-Whitney U test, Kruskal-Wallis test, and the ANOVA test were used, and a value of p < 0.05 was considered statistically significant. Demographic, clinical and pathohistological characteristics of renal tumors (patient gender, tumor size, tumor type, nuclear grade, and TNM stage of the disease) were examined in relation to the presence and localization of the co-expression of NCAM and FGFR1.

RESULTS

The analysis of 100 tumors, of which 68 were found in male patients and 32 in female patients, we recorded the simultaneous expression of NCAM and FGFR1 in 77 tumors (87.8%).

The NCAM molecule was observed on the membrane and in the cytosol, while FGFR1 included nuclear distribution in addition to these localizations.

In most pathohistological types, the frequency of co-expression was in the 80% – 100% range, while of the two Bellini duct carcinomas, only one showed simultaneous expression of NCAM and FGFR1 (Table 1).

Table 1. Pathohistological characteristics of renal tumors in relation to the presence of FGFR1-NCAM co-expression

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We observed that the increase in the occurrence of co-expression followed the increase in nuclear grade, although without statistical significance, and that all tumors with the highest nuclear grade simultaneously expressed these molecules (Table 1).

With an increasing T stage, an increase in the frequency of simultaneous expression of NCAM and FGFR1 in renal tumors was observed. Among high stage tumors (T3 and T4), only one tumor showed no co-expression, while co-expression was absent in 22.9% of T1 and T2 stage tumors. However, there was no statistically significant difference (Table 1).

Since data on nodal and systemic metastases for a larger number of samples were not available to us, we were unable to examine the relationship between their occurrence and the presence of co-expression. However, we observed that among the tumors for which we had obtained this data, all tumors with metastases, as well as all tumors without metastases, showed co-expression (Table 1).

We observed the presence of membranous expression of both NCAM and FGFR1 in only 59% of tumors, with great variations depending on the pathohistological type of the tumor. We did not observe membranous co-expression in any tumor among the collecting duct carcinomas, while among oncocytomas it was present in only one patient, whereas in all other types of tumors, co-expression was present with a frequency greater than 50%, as shown in Table 2. Figure 1 shows different patterns of NCAM and FGFR1 expression.

Table 2. Pathohistological characteristics of renal tumors in relation to the presence of FGFR1-NCAM co-expression

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Figure 1. Representation of membrane co-expression of NCAM (A) and FGFR1 (B) molecules in clear cell RCC and of cytoplasmic immunoreactivity of both molecules in oncocytoma (C – NCAM, D – FGFR1)

No association between nuclear grade and membranous co-expression was observed, but it was noted that the increase in T stage was followed by an increase in the percentage of tumors that had both molecules on the membranes, although there was no statistically significant difference (Table 2).

The examination of the relationship between tumor size and localization of NCAM and FGFR1 co-expression showed that renal tumors without membranous co-expression were, on average, slightly smaller in size (6.3 ± 2.7) than those with membranous positivity (6.9 ± 4.3), p = 0.390.

By analyzing the localization of the expression of each of these two molecules, we saw that they had very similar distribution. Tumors with membranous expression of NCAM also expressed FGFR1 on the membranes in 83% of cases, while the expression of FGFR1 on the membrane was accompanied by membranous expression of NCAM in 86% of the cases. It is interesting that all tumors in whose nucleus we found FGFR1 molecules, had both FGFR1 and NCAM molecules on the membrane surface.

DISCUSSION

Carcinogenesis is a multistage process that often culminates in the invasion of tumor cells into the surrounding tissue and blood vessels, thus contributing to their dissemination to distant tissues. The discovery of molecular interactions that enable the initiation and progression of this process would greatly facilitate the defining of key links, which could be the focus of targeted treatment.

Jimbo et al. found that NCAM in various tumor cells induces the production of a protein that prevents the attachment of tumor cells to the matrix and the basement membrane [29]. These authors transferred tumor cells expressing this protein to one group of experimental animals, while they transferred cells that did not possess this protein to the other group of experimental animals. The number of animals developing tumors after transfer was significantly lower in the first group than in the second group. These results indicate that NCAM, via another protein whose expression it is responsible for, has a negative effect on the processes crucial for the dissemination of the malignant process.

On the other hand, there are data indicating that the aggressiveness of neuroblastoma and neuroendocrine tumors increases with the presence of the NCAM protein [30],[31]. These seemingly contradictory results indicate that for the assessment of the biological behavior of tumors it may not be useful to examine the independent expression of this molecule, but that other molecules, with which NCAM enters into various interactions that lead to the stimulation or inhibition of various processes, are also important. Thus, it was observed that the colocalization of the NCAM molecule and aldehyde dehydrogenase 1 (ALDH1) in the blastema component of Wilms’ tumor occurs in 33% of cases, and it was found that this immunomorphological profile significantly affects the occurrence of metastases, disease recurrence, and patient death, as well as that it determines the response to the ifosfamide-carboplatin-etoposide (ICE) chemotherapy protocol [22]. In their study, Yang and Lu showed that co-expression of CCND1 and FGFR1 molecules exists in lung cancer, and that FGFR1 promotes EMT [21]. Examining pleuropulmonary blastoma cells, Shukrun and Golan observed that treatment with anti-NCAM immunoconjugate suppresses the growth of tumor cells in this tumor [23]. In their study, Egbivwie and Cockle observed that increased expression of FGFR1 among astrocytomas in the pediatric population was associated with age, location, and tumor grade, while membrane expression of pFGFR1 was associated with malignancy and tumor grade [27].

It is known that in non-invasive tumors FGFR1 stimulates growth and proliferation, while in invasive tumors it also stimulates the process of migration [32]. Interactions between FGFR1 and NCAM molecules were described for the first time in neurons [16], and were later described in other tissues [17],[18]. It has been shown that the interaction between these two molecules on the membrane of fibroblasts stimulates the migration of these cells [28], while a study performed on experimental cell cultures of epithelial ovarian cancer indicated that the activation of the FGFR1 molecule by the NCAM molecule increases the invasiveness of tumor cells [19].

Examining the influence of the interaction between these two molecules on the invasiveness of ovarian cancer, Colombo and Callavaro induced the expression of the NCAM protein in cell lines expressing FGFR1, which led to the transformation of indolent cancer to invasive carcinoma. However, the induction of the expression of the NCAM protein, modified so that it does not possess the FGFR1 binding domain, did not affect the behavior of the cancer [33], thus showing that the interactions between these two molecules, which have been described thus far only on the surface of the cell membrane, are significant for tumor aggressiveness. In our study, in addition to numerous cancers, co-expression of NCAM and FGFR1 was also detected in all oncocytomas. However, the pattern of this co-expression in benign tumors was exclusively linked to cytoplasmic localization. Therefore, we could say that, despite the presence of both molecules, their interaction was absent in oncocytomas, because membrane immunopositivity was exclusively a characteristic of malignant tumors of renal cell origin.

Colombo and Callavaro also found that the co-expression of NCAM and FGFR1 was most pronounced in cells located at the very periphery of the tumor. They understood this to speak in favor of the hypothesis that the co-expression of these molecules stimulates migration and adhesion, processes crucial for tumor metastases. For the majority of patients in our study information on the presence of regional and systemic metastases of renal tumors was lacking. However, analyzing the available data, we did not observe an association between the presence of metastases and membranous co-expression of NCAM and FGFR1. Bearing in mind the importance of tumor size in determining the stage of disease [34], we could assume that membranous co-expression of NCAM and FGFR1 is an immunomorphological substrate of local tumor growth. Thus, the increase in the frequency of membranous co-expression of the analyzed proteins was accompanied by an increase in the T stage of renal tumors, which could indirectly indicate a greater propensity of NCAM-FGFR1 positive tumors to metastasize, since the TNM classification of tumors is important, not only when deciding on a therapeutic approach, but it also has an impact on the prognosis of the disease and indicates the possibility of metastasis [35].

A study by Ronkainen et al. performed on different pathohistological types of RCC, including clear cell, papillary and chromophobe carcinoma, examined the expression of NCAM molecules. In this study, no correlation was observed between NCAM expression and tumor type, grade or stage [10]. The fact that the simultaneous expression of other molecules, which could interact with NCAM in processes essential for tumor progression, was not examined in this study could explain the apparent discrepancy between the conclusions of this study and our results.

Daniel et al. claimed that NCAM-positive tumors are more aggressive and that they more often metastasize to nervous and neuroendocrine – NCAM-positive tissues, such as the adrenal gland and the central nervous system. They described membranous expression in clear cell but not in papillary and chromophobe RCCs [36]. On the other hand, in most tumors of the same pathohistological types, we observed not only independent NCAM expression, but also co-expression with FGFR1.

Keresztes and Boonstra pointed out long ago the potential importance of the nuclear localization of different growth factor receptors. They highlighted the fact that the nuclear presence of receptors and their ligands leads to an increase in proliferation [37]. Chioni and Grose, working on breast cancers, discovered that granzyme B is responsible for the delivery of FGFR1 to the cell nucleus and that blocking it eliminates the effect of FGFR1 activation on proliferation, as well as that FGFR1 can act as a transcription factor for some genes responsible for proliferation [38]. All renal tumors in whose nuclei we detected FGFR1 showed co-expression of FGFR1 and NCAM molecules on the membrane. Given the data that FGFR1 acts as a transcription factor for some genes, we cannot rule out the possibility that membranous expression of the NCAM protein is the result of this kind of FGFR1 activity, but this requires additional research. Also, it is possible that the expression of FGFR1 in the nucleus is responsible for the progression of renal cancer, as shown in breast tumors, by a mechanism that does not involve interactions with the NCAM protein [39].

Investigations of various molecular interactions in tumor pathology aim to define the key processes important in the initiation and progression of tumor growth, the ability to invade surrounding tissues, and tumor metastasis. It was recently discovered that the synthetic substance PD173074, which is a potent FGFR1 inhibitor, prevents the proliferation of tumor cells and induces a change in their morphology through the induction of mesenchymal-epithelial transformation, reducing invasiveness and tumor growth [40],[41]. Considering the above conclusions about the effect of the NCAM-FGFR1 interaction, further research could open the question of the possibility of applying the FGFR1 inhibitor (PD173074) in order to slow down the local growth of renal tumors and reduce their invasive potential.

CONCLUSION

It is possible that only membranous co-expression of NCAM and FGFR1 affects more aggressive biological behavior of a tumor, thus affecting the stage of the disease, and that only this pattern of co-expression is significant for the assessment of their biological activity, which was not observed in any benign tumor, despite the presence of cytoplasmic co-expression. It is possible that in a smaller number of patients the phenomenon of membranous NCAM-FGFR1 co-expression is the result of the presence of FGFR1 molecules in the nucleus of the tumor cells. It is necessary to perform further studies, on a larger number of patients, in order to make a detailed analysis of the significance of the co-expression of NCAM and FGFR1 in patients with renal tumors.

  • Conflict of interest:
    None declared.

Informations

Volume 4 No 4

December 2023

Pages 349-359
  • Keywords:
    RCT, RCC, NCAM, FGFR1, renal tumors
  • Received:
    08 September 2023
  • Revised:
    23 September 2023
  • Accepted:
    28 September 2023
  • Online first:
    25 December 2023
  • DOI:
  • Cite this article:
    Filipović I, Mioljević A, Nikolić G, Filipović J, Radojević Škodrić S, Bogosavljević N, et al. Possible impact of NCAM and FGFR1 molecule expression patterns on the biological behavior of renal cell carcinoma. Serbian Journal of the Medical Chamber. 2023;4(4):347-57. doi: 10.5937/smclk4-46414
Corresponding author

Maja Životić
Institute of Pathology, Serbia, Faculty of Medicine, University of Belgrade
1 Dr Subotića starijeg Street, 11129 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


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    41. Nguyen PT, Tsunematsu T, Yanagisawa S, Kudo Y, Miyauchi M, Kamata N, et al. The FGFR1 inhibitor PD173074 induces mesenchymal-epithelial transition through the transcription factor AP-1. Br J Cancer. 2013 Oct 15;109(8):2248- 58. doi: 10.1038/bjc.2013.550. [CROSSREF]


REFERENCES

1. Levi F, Ferlay J, Galeone C, Lucchini F, Negri E, Boyle P, et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int. 2008 Apr;101(8):949-58. doi: 10.1111/j.1464-410X.2008.07451.x. [CROSSREF]

2. Lipworth L, Tarone RE, Lund L, McLaughlin JK. Epidemiologic characteristics and risk factors for renal cell cancer. Clin Epidemiol. 2009 Aug 9;1:33-43. doi: 10.2147/clep.s4759. [CROSSREF]

3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. doi: 10.3322/CA.2007.0010. [CROSSREF]

4. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007 Mar;18(3):581-92. doi: 10.1093/annonc/mdl498. [CROSSREF]

5. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009 Mar 28;373(9669):1119-32. doi: 10.1016/S0140-6736(09)60229-4. [CROSSREF]

6. Trpkov K, Yilmaz A, Uzer D, Dishongh KM, Quick CM, Bismar TA, et al. Renal oncocytoma revisited: a clinicopathological study of 109 cases with emphasis on problematic diagnostic features. Histopathology. 2010 Dec;57(6):893- 906. doi: 10.1111/j.1365-2559.2010.03726.x. [CROSSREF]

7. Penticuff JC, Kyprianou N. Therapeutic challenges in renal cell carcinoma. Am J Clin Exp Urol. 2015 Aug 8;3(2):77-90. [HTTP]

8. Klein G, Langegger M, Goridis C, Ekblom P. Neural cell adhesion molecules during embryonic induction and development of the kidney. Development. 1988 Apr;102(4):749-61. doi: 10.1242/dev.102.4.749. [CROSSREF]

9. Marković-Lipkovski J, Müller CA, Klein G, Flad T, Klatt T, Blaschke S, et al. Neural cell adhesion molecule expression on renal interstitial cells. Nephrol Dial Transplant. 2007 Jun;22(6):1558-66. doi: 10.1093/ndt/gfm006. [CROSSREF]

10. Ronkainen H, Soini Y, Vaarala MH, Kauppila S, Hirvikoski P. Evaluation of neuroendocrine markers in renal cell carcinoma. Diagn Pathol. 2010 May 12;5:28. doi: 10.1186/1746-1596-5-28. [CROSSREF]

11. Bade LK, Goldberg JE, Dehut HA, Hall MK, Schwertfeger KL. Mammary tumorigenesis induced by fibroblast growth factor receptor 1 requires activation of the epidermal growth factor receptor. J Cell Sci. 2011 Sep 15;124(Pt 18):3106-17. doi: 10.1242/jcs.082651. [CROSSREF]

12. Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005 Apr;16(2):159-78. doi: 10.1016/j.cytogfr.2005.01.004. [CROSSREF]

13. Xian W, Schwertfeger KL, Rosen JM. Distinct roles of fibroblast growth factor receptor 1 and 2 in regulating cell survival and epithelial-mesenchymal transition. Mol Endocrinol. 2007 Apr;21(4):987-1000. doi: 10.1210/me.2006-0518. [CROSSREF]

14. Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49. doi: 10.1016/j.cytogfr.2005.01.001. [CROSSREF]

15. Kiselyov VV, Skladchikova G, Hinsby AM, Jensen PH, Kulahin N, Soroka V, et al. Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure. 2003 Jun;11(6):691-701. doi: 10.1016/s0969-2126(03)00096-0. [CROSSREF]

16. Williams EJ, Furness J, Walsh FS, Doherty P. Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin. Neuron. 1994 Sep;13(3):583-94. doi: 10.1016/0896-6273(94)90027-2. [CROSSREF]

17. Francavilla C, Cattaneo P, Berezin V, Bock E, Ami D, de Marco A, et al. The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking. J Cell Biol. 2009 Dec 28;187(7):1101-16. doi: 10.1083/jcb.200903030. [CROSSREF]

18. Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol. 2001 Jul;3(7):650-7. doi: 10.1038/35083041. [CROSSREF]

19. Zecchini S, Bombardelli L, Decio A, Bianchi M, Mazzarol G, Sanguineti F, et al. The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling. EMBO Mol Med. 2011 Aug;3(8):480-94. doi: 10.1002/emmm.201100152. [CROSSREF]

20. Sowparani S, Mahalakshmi P, Sweety JP, Francis AP, Dhanalekshmi UM, Selvasudha N. Ubiquitous Neural Cell Adhesion Molecule (NCAM): Potential Mechanism and Valorisation in Cancer Pathophysiology, Drug Targeting and Molecular Transductions. Mol Neurobiol. 2022 Sep;59(9):5902-5924. doi: 10.1007/s12035-022-02954-9. [CROSSREF]

21. Yang Y, Lu T, Li Z, Lu S. FGFR1 regulates proliferation and metastasis by targeting CCND1 in FGFR1 amplified lung cancer. Cell Adh Migr. 2020 Dec;14(1):82- 95. doi: 10.1080/19336918.2020.1766308.  [CROSSREF]

22. Raved D, Tokatly-Latzer I, Anafi L, Harari-Steinberg O, Barshack I, Dekel B, et al. Blastemal NCAM+ALDH1+ Wilms’ tumor cancer stem cells correlate with disease progression and poor clinical outcome: A pilot study. Pathol Res Pract. 2019 Aug;215(8):152491. doi: 10.1016/j.prp.2019.152491. [CROSSREF]

23. Shukrun R, Golan H, Caspi R, Pode-Shakked N, Pleniceanu O, Vax E, et al. NCAM1/FGF module serves as a putative pleuropulmonary blastoma therapeutic target. Oncogenesis. 2019 Sep 2;8(9):48. doi: 10.1038/s41389-019-0156-9. [CROSSREF]

24. Ardizzone A, Scuderi SA, Giuffrida D, Colarossi C, Puglisi C, Campolo M, et al. Role of Fibroblast Growth Factors Receptors (FGFRs) in Brain Tumors, Focus on Astrocytoma and Glioblastoma. Cancers (Basel). 2020 Dec 18;12(12):3825. doi: 10.3390/cancers12123825. [CROSSREF]

25. Krook MA, Reeser JW, Ernst G, Barker H, Wilberding M, Li G, et al. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. Br J Cancer. 2021 Mar;124(5):880- 892. doi: 10.1038/s41416-020-01157-0. [CROSSREF]

26. Ferguson HR, Smith MP, Francavilla C. Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling. Cells. 2021 May 14;10(5):1201. doi: 10.3390/cells10051201. [CROSSREF]

27. Egbivwie N, Cockle JV, Humphries M, Ismail A, Esteves F, Taylor C, et al. FGFR1 Expression and Role in Migration in Low and High Grade Pediatric Gliomas. Front Oncol. 2019 Mar 13;9:103. doi: 10.3389/fonc.2019.00103.  [CROSSREF]

28. Bogatyrova O, Mattsson JSM, Ross EM, Sanderson MP, Backman M, Botling J, et al. FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response. Eur J Cancer. 2021 Jul;151:136-149. doi: 10.1016/j.ejca.2021.04.005. [CROSSREF]

29. Jimbo T, Nakayama J, Akahane K, Fukuda M. Effect of polysialic acid on the tumor xenografts implanted into nude mice. Int J Cancer. 2001 Oct 15;94(2):192-9. doi: 10.1002/ijc.1458.  [CROSSREF]

30. Glüer S, Schelp C, von Schweinitz D, Gerardy-Schahn R. Polysialylated neural cell adhesion molecule in childhood rhabdomyosarcoma. Pediatr Res. 1998 Jan;43(1):145-7. doi: 10.1203/00006450-199801000-00022. [CROSSREF]

31. Seidenfaden R, Krauter A, Schertzinger F, Gerardy-Schahn R, Hildebrandt H. Polysialic acid directs tumor cell growth by controlling heterophilic neural cell adhesion molecule interactions. Mol Cell Biol. 2003 Aug;23(16):5908-18. doi: 10.1128/MCB.23.16.5908-5918.2003. [CROSSREF]

32. Tomlinson DC, Baxter EW, Loadman PM, Hull MA, Knowles MA. FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCγ/COX-2-mediated mechanisms. PLoS One. 2012;7(6):e38972. doi: 10.1371/journal.pone.0038972. [CROSSREF]

33. Colombo N, Cavallaro U. The interplay between NCAM and FGFR signalling underlies ovarian cancer progression. Ecancermedicalscience. 2011;5:226. doi: 10.3332/ecancer.2011.226. [CROSSREF]

34. Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015 May;67(5):913-24. doi: 10.1016/j.eururo.2015.01.005.  [CROSSREF]

35. Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997 Nov 1;80(9):1803-4. doi: 10.1002/(sici)1097-0142(19971101)80:9%3C1803::aid-cncr16%3E3.0.co;2-9 [CROSSREF]

36. Daniel L, Bouvier C, Chetaille B, Gouvernet J, Luccioni A, Rossi D, et al. Neural cell adhesion molecule expression in renal cell carcinomas: relation to metastatic behavior. Hum Pathol. 2003 Jun;34(6):528-32. doi: 10.1016/s0046-8177(03)00178-3. [CROSSREF]

37. Keresztes M, Boonstra J. Import(ance) of growth factors in(to) the nucleus. J Cell Biol. 1999 May 3;145(3):421-4. doi: 10.1083/jcb.145.3.421. [CROSSREF]

38. Chioni AM, Grose R. FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. J Cell Biol. 2012 Jun 11;197(6):801-17. doi: 10.1083/jcb.201108077. [CROSSREF]

39. Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998 Oct 15;17(20):5896-904. doi: 10.1093/emboj/17.20.5896. [CROSSREF]

40. Pardo OE, Latigo J, Jeffery RE, Nye E, Poulsom R, Spencer-Dene B, et al. The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo. Cancer Res. 2009 Nov 15;69(22):8645-51. doi: 10.1158/0008-5472.CAN-09-1576. [CROSSREF]

41. Nguyen PT, Tsunematsu T, Yanagisawa S, Kudo Y, Miyauchi M, Kamata N, et al. The FGFR1 inhibitor PD173074 induces mesenchymal-epithelial transition through the transcription factor AP-1. Br J Cancer. 2013 Oct 15;109(8):2248- 58. doi: 10.1038/bjc.2013.550. [CROSSREF]

1. Levi F, Ferlay J, Galeone C, Lucchini F, Negri E, Boyle P, et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int. 2008 Apr;101(8):949-58. doi: 10.1111/j.1464-410X.2008.07451.x. [CROSSREF]

2. Lipworth L, Tarone RE, Lund L, McLaughlin JK. Epidemiologic characteristics and risk factors for renal cell cancer. Clin Epidemiol. 2009 Aug 9;1:33-43. doi: 10.2147/clep.s4759. [CROSSREF]

3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. doi: 10.3322/CA.2007.0010. [CROSSREF]

4. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007 Mar;18(3):581-92. doi: 10.1093/annonc/mdl498. [CROSSREF]

5. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009 Mar 28;373(9669):1119-32. doi: 10.1016/S0140-6736(09)60229-4. [CROSSREF]

6. Trpkov K, Yilmaz A, Uzer D, Dishongh KM, Quick CM, Bismar TA, et al. Renal oncocytoma revisited: a clinicopathological study of 109 cases with emphasis on problematic diagnostic features. Histopathology. 2010 Dec;57(6):893- 906. doi: 10.1111/j.1365-2559.2010.03726.x. [CROSSREF]

7. Penticuff JC, Kyprianou N. Therapeutic challenges in renal cell carcinoma. Am J Clin Exp Urol. 2015 Aug 8;3(2):77-90. [HTTP]

8. Klein G, Langegger M, Goridis C, Ekblom P. Neural cell adhesion molecules during embryonic induction and development of the kidney. Development. 1988 Apr;102(4):749-61. doi: 10.1242/dev.102.4.749. [CROSSREF]

9. Marković-Lipkovski J, Müller CA, Klein G, Flad T, Klatt T, Blaschke S, et al. Neural cell adhesion molecule expression on renal interstitial cells. Nephrol Dial Transplant. 2007 Jun;22(6):1558-66. doi: 10.1093/ndt/gfm006. [CROSSREF]

10. Ronkainen H, Soini Y, Vaarala MH, Kauppila S, Hirvikoski P. Evaluation of neuroendocrine markers in renal cell carcinoma. Diagn Pathol. 2010 May 12;5:28. doi: 10.1186/1746-1596-5-28. [CROSSREF]

11. Bade LK, Goldberg JE, Dehut HA, Hall MK, Schwertfeger KL. Mammary tumorigenesis induced by fibroblast growth factor receptor 1 requires activation of the epidermal growth factor receptor. J Cell Sci. 2011 Sep 15;124(Pt 18):3106-17. doi: 10.1242/jcs.082651. [CROSSREF]

12. Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005 Apr;16(2):159-78. doi: 10.1016/j.cytogfr.2005.01.004. [CROSSREF]

13. Xian W, Schwertfeger KL, Rosen JM. Distinct roles of fibroblast growth factor receptor 1 and 2 in regulating cell survival and epithelial-mesenchymal transition. Mol Endocrinol. 2007 Apr;21(4):987-1000. doi: 10.1210/me.2006-0518. [CROSSREF]

14. Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49. doi: 10.1016/j.cytogfr.2005.01.001. [CROSSREF]

15. Kiselyov VV, Skladchikova G, Hinsby AM, Jensen PH, Kulahin N, Soroka V, et al. Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure. 2003 Jun;11(6):691-701. doi: 10.1016/s0969-2126(03)00096-0. [CROSSREF]

16. Williams EJ, Furness J, Walsh FS, Doherty P. Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin. Neuron. 1994 Sep;13(3):583-94. doi: 10.1016/0896-6273(94)90027-2. [CROSSREF]

17. Francavilla C, Cattaneo P, Berezin V, Bock E, Ami D, de Marco A, et al. The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking. J Cell Biol. 2009 Dec 28;187(7):1101-16. doi: 10.1083/jcb.200903030. [CROSSREF]

18. Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol. 2001 Jul;3(7):650-7. doi: 10.1038/35083041. [CROSSREF]

19. Zecchini S, Bombardelli L, Decio A, Bianchi M, Mazzarol G, Sanguineti F, et al. The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling. EMBO Mol Med. 2011 Aug;3(8):480-94. doi: 10.1002/emmm.201100152. [CROSSREF]

20. Sowparani S, Mahalakshmi P, Sweety JP, Francis AP, Dhanalekshmi UM, Selvasudha N. Ubiquitous Neural Cell Adhesion Molecule (NCAM): Potential Mechanism and Valorisation in Cancer Pathophysiology, Drug Targeting and Molecular Transductions. Mol Neurobiol. 2022 Sep;59(9):5902-5924. doi: 10.1007/s12035-022-02954-9. [CROSSREF]

21. Yang Y, Lu T, Li Z, Lu S. FGFR1 regulates proliferation and metastasis by targeting CCND1 in FGFR1 amplified lung cancer. Cell Adh Migr. 2020 Dec;14(1):82- 95. doi: 10.1080/19336918.2020.1766308.  [CROSSREF]

22. Raved D, Tokatly-Latzer I, Anafi L, Harari-Steinberg O, Barshack I, Dekel B, et al. Blastemal NCAM+ALDH1+ Wilms’ tumor cancer stem cells correlate with disease progression and poor clinical outcome: A pilot study. Pathol Res Pract. 2019 Aug;215(8):152491. doi: 10.1016/j.prp.2019.152491. [CROSSREF]

23. Shukrun R, Golan H, Caspi R, Pode-Shakked N, Pleniceanu O, Vax E, et al. NCAM1/FGF module serves as a putative pleuropulmonary blastoma therapeutic target. Oncogenesis. 2019 Sep 2;8(9):48. doi: 10.1038/s41389-019-0156-9. [CROSSREF]

24. Ardizzone A, Scuderi SA, Giuffrida D, Colarossi C, Puglisi C, Campolo M, et al. Role of Fibroblast Growth Factors Receptors (FGFRs) in Brain Tumors, Focus on Astrocytoma and Glioblastoma. Cancers (Basel). 2020 Dec 18;12(12):3825. doi: 10.3390/cancers12123825. [CROSSREF]

25. Krook MA, Reeser JW, Ernst G, Barker H, Wilberding M, Li G, et al. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. Br J Cancer. 2021 Mar;124(5):880- 892. doi: 10.1038/s41416-020-01157-0. [CROSSREF]

26. Ferguson HR, Smith MP, Francavilla C. Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling. Cells. 2021 May 14;10(5):1201. doi: 10.3390/cells10051201. [CROSSREF]

27. Egbivwie N, Cockle JV, Humphries M, Ismail A, Esteves F, Taylor C, et al. FGFR1 Expression and Role in Migration in Low and High Grade Pediatric Gliomas. Front Oncol. 2019 Mar 13;9:103. doi: 10.3389/fonc.2019.00103.  [CROSSREF]

28. Bogatyrova O, Mattsson JSM, Ross EM, Sanderson MP, Backman M, Botling J, et al. FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response. Eur J Cancer. 2021 Jul;151:136-149. doi: 10.1016/j.ejca.2021.04.005. [CROSSREF]

29. Jimbo T, Nakayama J, Akahane K, Fukuda M. Effect of polysialic acid on the tumor xenografts implanted into nude mice. Int J Cancer. 2001 Oct 15;94(2):192-9. doi: 10.1002/ijc.1458.  [CROSSREF]

30. Glüer S, Schelp C, von Schweinitz D, Gerardy-Schahn R. Polysialylated neural cell adhesion molecule in childhood rhabdomyosarcoma. Pediatr Res. 1998 Jan;43(1):145-7. doi: 10.1203/00006450-199801000-00022. [CROSSREF]

31. Seidenfaden R, Krauter A, Schertzinger F, Gerardy-Schahn R, Hildebrandt H. Polysialic acid directs tumor cell growth by controlling heterophilic neural cell adhesion molecule interactions. Mol Cell Biol. 2003 Aug;23(16):5908-18. doi: 10.1128/MCB.23.16.5908-5918.2003. [CROSSREF]

32. Tomlinson DC, Baxter EW, Loadman PM, Hull MA, Knowles MA. FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCγ/COX-2-mediated mechanisms. PLoS One. 2012;7(6):e38972. doi: 10.1371/journal.pone.0038972. [CROSSREF]

33. Colombo N, Cavallaro U. The interplay between NCAM and FGFR signalling underlies ovarian cancer progression. Ecancermedicalscience. 2011;5:226. doi: 10.3332/ecancer.2011.226. [CROSSREF]

34. Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015 May;67(5):913-24. doi: 10.1016/j.eururo.2015.01.005.  [CROSSREF]

35. Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997 Nov 1;80(9):1803-4. doi: 10.1002/(sici)1097-0142(19971101)80:9%3C1803::aid-cncr16%3E3.0.co;2-9 [CROSSREF]

36. Daniel L, Bouvier C, Chetaille B, Gouvernet J, Luccioni A, Rossi D, et al. Neural cell adhesion molecule expression in renal cell carcinomas: relation to metastatic behavior. Hum Pathol. 2003 Jun;34(6):528-32. doi: 10.1016/s0046-8177(03)00178-3. [CROSSREF]

37. Keresztes M, Boonstra J. Import(ance) of growth factors in(to) the nucleus. J Cell Biol. 1999 May 3;145(3):421-4. doi: 10.1083/jcb.145.3.421. [CROSSREF]

38. Chioni AM, Grose R. FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. J Cell Biol. 2012 Jun 11;197(6):801-17. doi: 10.1083/jcb.201108077. [CROSSREF]

39. Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998 Oct 15;17(20):5896-904. doi: 10.1093/emboj/17.20.5896. [CROSSREF]

40. Pardo OE, Latigo J, Jeffery RE, Nye E, Poulsom R, Spencer-Dene B, et al. The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo. Cancer Res. 2009 Nov 15;69(22):8645-51. doi: 10.1158/0008-5472.CAN-09-1576. [CROSSREF]

41. Nguyen PT, Tsunematsu T, Yanagisawa S, Kudo Y, Miyauchi M, Kamata N, et al. The FGFR1 inhibitor PD173074 induces mesenchymal-epithelial transition through the transcription factor AP-1. Br J Cancer. 2013 Oct 15;109(8):2248- 58. doi: 10.1038/bjc.2013.550. [CROSSREF]


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