Skip to main content

Main menu

  • Home
  • Current Issue
  • Archive
  • Info for
    • Authors
    • Editorial Policies
    • Subscribers
    • Advertisers
    • Editorial Board
  • Other Publications
    • In Vivo
    • Cancer Genomics & Proteomics
    • Cancer Diagnosis & Prognosis
  • More
    • IIAR
    • Conferences
    • 2008 Nobel Laureates
  • About Us
    • General Policy
    • Contact
  • Other Publications
    • Anticancer Research
    • In Vivo
    • Cancer Genomics & Proteomics

User menu

  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Anticancer Research
  • Other Publications
    • Anticancer Research
    • In Vivo
    • Cancer Genomics & Proteomics
  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Anticancer Research

Advanced Search

  • Home
  • Current Issue
  • Archive
  • Info for
    • Authors
    • Editorial Policies
    • Subscribers
    • Advertisers
    • Editorial Board
  • Other Publications
    • In Vivo
    • Cancer Genomics & Proteomics
    • Cancer Diagnosis & Prognosis
  • More
    • IIAR
    • Conferences
    • 2008 Nobel Laureates
  • About Us
    • General Policy
    • Contact
  • Visit us on Facebook
  • Follow us on Linkedin
Research ArticleExperimental Studies

Expression of IGF-IEc Isoform in Renal Cell Carcinoma Tissues

FANI MICHALOPOULOU, CONSTANTINA PETRAKI, ANASTASSIOS PHILIPPOU, ANTONIS ANALITIS, PAVLOS MSAOUEL and MICHAEL KOUTSILIERIS
Anticancer Research November 2020, 40 (11) 6213-6219; DOI: https://doi.org/10.21873/anticanres.14641
FANI MICHALOPOULOU
1Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
CONSTANTINA PETRAKI
2Department of Pathology, Evangelismos General Hospital, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
ANASTASSIOS PHILIPPOU
1Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
ANTONIS ANALITIS
3Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
PAVLOS MSAOUEL
4Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, U.S.A.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
MICHAEL KOUTSILIERIS
1Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: mkoutsil@med.uoa.gr
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Background/Aim: Insulin-like growth factor-I (IGF-I) regulates various aspects of cancer biology. There is a growing body of evidence regarding the potential distinct role of IGF-I isoforms, particularly of IGF-IEc, in the pathophysiology of various human cancer types, however, there are no studies which examined the expression of the different IGF-I isoforms in renal cell carcinoma (RCC). This study aimed to characterize the expression of IGF-IEc in human RCC tissues and investigated whether its expression is associated with the histopathological type of RCC as well as with the overall survival of patients. Materials and Methods: Formalin-fixed paraffin-embedded renal tissue samples from 94 patients (58 males and 36 females) were assessed for IGF-IEc expression by immunohistochemistry. Results: RCC tissues showed mainly cytoplasmic IGF-IEc staining but immunoreactivity of IGF-IEc was also localized in the cell membrane. Significantly lower IGF-IEc expression was found in clear cell RCC vs. all other histological types (p=0.010), and this remained significant after adjusting for tumor size, grade, stage, and mitotic index (p<0.05). No association was found between IGF-IEc expression level and overall survival of patients with RCC. Conclusion: The differential expression of IGF-IEc isoform among the RCC histopathological types may indicate its histological type-specific regulation and possibly suggests a discrete biological role of this isoform in the pathophysiology of RCC.

  • Insulin-like growth factor-I
  • IGF-I
  • IGF-IEc
  • renal cancer
  • clear cell RCC

Renal cell carcinoma (RCC) is the most common kidney malignancy, affecting men more than women, and metastatic disease at presentation occurs in up to one-third of patients. The pathological stage (size of the tumor and the extent of invasion), grade, and histological cell type are widely used in clinical practice for the prognosis of RCC (1). In particular, clear cell is the most common histological type of RCC accounting for 60-70% of cases (2). It represents a genetically and histologically diverse group of cancers that includes chromophobe, papillary, unclassified RCC, and other rare subtypes such as renal medullary carcinoma (3-6).

Insulin-like growth factor-I (IGF-I) plays an important role in various aspects of cancer biology, such as cell growth, apoptosis resistance, cell differentiation and migration (7-10) and, thus, it has been implicated in the pathophysiology and prognosis of several human cancer types (11-14), including RCC (2, 15, 16). IGF-I is not only secreted by the liver, but is also produced by other organs such as skeletal muscle, kidney and brain (17-27). The IGF1 gene consists of six exons and can produce multiple heterogeneous transcripts via alternative splicing during its transcription, namely IGF-IEa, IGF-IEb, and IGF-IEc, which encode the corresponding IGF-I protein isoforms (24, 26). Mature IGF-I peptide represents the common bioactive product of all IGF-I isoforms (24, 28) and numerous studies have shown that this peptide is involved in cell survival and protection from apoptosis, as well as in the process of uncontrolled cell division, which generally characterizes cancer development (10, 29, 30). Various types of human cancer cells, such as prostate, breast and osteosarcoma (8, 31-35), have been found to be affected by these IGF-I functions, while IGF-I has also been shown to contribute to cancer cell migration (36), tumor aggressiveness (37, 38) and neovascularization (39).

Interestingly, a new component of the IGF bioregulatory system has recently been studied for its potential role in carcinogenesis, specifically, IGF-I isoforms (precursors). These undergo post-translational cleavage, generating the common mature IGF-I peptide but also different carboxyl-terminal extension (E-) peptides (24, 40) and there is a growing body of evidence regarding the potential role of IGF-I isoforms and their respective post-translational IGF-I products, other than mature peptide, in the pathophysiology of different cancer models both in vitro and in vivo (11, 13, 33, 34, 41-43). The differential regulation of the IGF-I isoforms in the pathophysiology of cancer (13, 33, 41) may imply their discrete biological roles, potentially via the putative Ea, Eb and Ec peptides (11, 18, 20, 33-35, 40, 44, 45). In particular, Ec peptide is a bioactive product of the IGF-IEc isoform and its action has been shown to be mediated via an IGF-I receptor-independent mechanism (11, 18-20, 33, 44) and has been postulated to be oncogenic (46).

However, to our knowledge, there are no studies examining the expression of the different IGF-I isoforms in RCC. Given the potentially distinct biological role, particularly of the IGF-IEc isoform and its post-translational product Ec peptide in different types of cancer (13, 33, 37, 38, 46), this study aimed to characterize the expression/localization of IGF-IEc in human renal cell carcinoma tissues and investigate whether its expression is associated with the histopathological type of RCC as well as with the overall survival of patients.

Materials and Methods

Ethical approval. A retrospective selection of primary renal carcinoma tissue diagnostic biopsy samples was performed from the archives of the Pathology Department of a General Hospital and this research approach was approved by the Ethics Committee of the Medical School of the National and Kapodistrian University of Athens (approval number: 781/29-9-2009), while all experimental procedures conformed to the Declaration of Helsinki.

Patients. Formaldehyde-fixed and paraffin wax-embedded renal tissue samples, derived from 94 patients, 58 males and 36 females, who underwent radical nephrectomy for histologically proven renal carcinoma within the time period from 1986 to 1998 were retrospectively selected from the archives of the Pathology Department of the “Evangelismos” General Hospital of Athens. Based on the official pathology reports, detailed information was recorded and analyzed, while all tissue specimens were further re-evaluated and confirmed by another pathologist. The patients were between 36 and 82 years of age and divided into different subgroups based on their age, sex, tumor location, invasion and size, histological type, grade and stage according to the 2016 World Health Organization/International Society of Urologic Pathologists classification (47).

Immunohistochemical analysis. Paraffin wax-embedded renal tissue samples were processed for paraffin sections as described elsewhere (18) and a Bondmax automated system (Leica Microsystems, Newcastle upon Tyne, UK) was used for the immunohistochemical (IHC) staining of the sections. The sections were then incubated with specific anti-human IGF-IEc antibody (48) at a dilution of 1:1,000 in phosphate-buffered saline, as previously described (18). Secondary biotinylated goat anti-rabbit IgG antibody (Dako Real EnVision, Glostrup, Denmark) was used and tissue sections were visualized under light microscopy. Prostate cancer biopsy sections were used as positive control (33), while control for the specificity of the reactions obtained in immunohistochemical analysis was performed by substituting the primary IGF-IEc antibody with the antibody diluent (phosphate-buffered saline) only (negative control). One representative tumor section per case was evaluated independently by two blinded pathologists, using intermediate-power light microscopy. Expression/localization of IGF-IEc was assessed and categorized as either grade 1 (weak intensity), grade 2 (moderate intensity) or grade 3 (strong intensity) according to both the intensity and distribution of the staining, while absence of staining was categorized as grade 0 (IGF-Ec-negative). The percentage distribution of each grade was multiplied by the corresponding number (0, 1, 2, or 3) and the summation of those products comprised the total IGF-IEc expression score of the sample (range of expression level: 0-300).

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table I.

Descriptive statistics of the patients' clinicopathological characteristics.

Statistical analysis. Data analysis was performed using Stata 13 statistical software (StataCorp. LP, College Station, TX, USA). Comparison of IGF-IEc expression between groups was performed using t-test or Man–Whitney test. Kolmogorov–Smirnov or Shapiro–Wilk test was used to evaluate normality. Multiple linear regression was used to test differences of IGF-IEc expression between groups after controlling for potential confounders. Cox proportional hazards model was used to investigate association between IGF-IEc and risk of death from cancer. Fine and Grey competing risks model (49) was applied to assess confounding by other causes of death. The shape of the association between IGF-IEc and risk of death from cancer was evaluated using natural cubic splines with four knots. All analyses were performed at a=5% level of statistical significance.

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Representative images of weak (A), moderate (B) and strong (C) immunohistochemical staining of renal cell carcinoma tissue sections using the specific antibody to human insulin-like growth factor (IGF)-IEc. Note the positive (brown) staining with mainly cytoplasmic localization. Specificity of the immunohistochemical detection of IGF-IEc was confirmed by the absence of immunoreactivity in the control (D) (see text for details; magnification ×200).

Results

Table I lists the clinicopathological characteristics of the patients included in the present study. Representative samples stained with the IGF-IEc specific antibody are shown in Figure 1. RCC tissues showed mainly cytoplasmic IGF-IEc staining but immunoreactivity of IGF-IEc was also localized in the cell membrane. The median IGF-IEc expression score overall was 184 (range=40-300; 25th and 75th percentile values of 125 and 215, respectively). Five out of 94 samples (~5%) were completely negative for IGF-IEc.

IGF-IEc expression in clear cell RCC versus all other histological types was significantly lower (Table II, p=0.010; Figure 2). This finding remained significant after adjusting for tumor size, grade, stage, and mitotic index (p<0.05). Higher IGF-IEc levels were found in sarcomatoid (five cases) compared to other cell types although not a statistically significant finding (p=0.420) (Table II).

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table II.

Comparison of insulin-like growth factor (IGF)-IEc expression score (mean±SD) by histological type.

The Cox proportional hazards as well as Fine and Grey competing risks models did not suggest a clinically meaningful association between IGF-IEc level and risk of death from cancer [hazard ratio (95% confidence interval) of 1.001 (0.994-1.007) and 1.000 (0.994-1.007), respectively] under assumption of a linear association. When the linear association assumption was relaxed, a non-linear, non-significant (p=0.470) association was identified between IGF-IEc level and overall survival, the shape of which was polynomial as depicted in Figure 3.

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Box plots representing the distribution of insulin-like growth factor (IGF)-IEc expression values by cell type. The line within each box is the median value, upper and lower whiskers represent the minimum and the maximum values, and the box shows the interquartile range.

Discussion

The present study investigated the IHC expression/localization of the IGF-IEc isoform in different histological types of RCC tissues, revealing significant differences in the IGF-IEc levels between clear cell RCC and all other histological types and these differences remained significant after adjusting for tumor size, grade, stage or mitotic index, alternatively. To our best knowledge, this is the first study investigating the expression pattern of IGF-IEc isoform in different types of renal cancer, showing an association between low expression of IGF-IEc and specific RCC pathology. Moreover, it was demonstrated that its expression/localization in RCC tissues was mainly cytoplasmic, while no significant association was found between IGF-IEc level and overall survival of patients with RCC.

IGF-I has been shown to play an important role in cell proliferation and protection from apoptosis in a wide variety of cancer types such as of the prostate, breast, lung, colon, stomach, esophagus, sarcoma, leukemia, liver, pancreas, thyroid, brain, ovary and uterus (cervix and endometrium) (50-53). In particular, studies that have addressed the role of IGF-I or its receptor (IGF-IR) in RCC (2, 15, 16, 54-56) implicated the IGF-I system in the development and progression of RCC, specifically reporting IGF-IR expression to be increased in RCC, which in its turn was associated with poorer cancer-specific survival and increased risk of death compared to patients who had tumors with low IGF-IR expression (2, 15).

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

The polynomial shape of the association revealed between score for insulin-like growth factor (IGF)-IEc isoform expression and risk of cancer death in patients with renal cell carcinoma.

Interestingly, there has been a growing interest in the investigation of the expression pattern of the IGF-I isoforms in cancer, as well as in other conditions and pathologies (13, 18-20, 25, 33, 57, 58), since a differential regulation of the IGF-I isoforms in such pathologies may indicate a distinct biological role for the different IGF-I precursor polypeptides or their extension peptides (i.e. Ea, Eb and Ec). The role of the IGF-I E peptides remains as yet unclear (24), nevertheless initial evidence was provided recently that Ec peptide is differentially regulated during muscle regeneration in humans (40), while synthetic Ec peptide was documented to possess bioactivity (11, 18-20, 44, 59) and its overexpression in PC-3 prostate cancer cells was found to increase their oncogenic potential in mice (46).

Specifically, the mitogenic effect of an E domain-related product of the IGF-IEc isoform in human prostate cancer, breast cancer, endometrial and osteosarcoma cells has been documented in previous studies of our group in vitro (18, 33-35, 46). Moreover, a potential role of the IGF-IEc isoform in the pathophysiology of bladder cancer (13), thyroid cancer (38) and neuroendocrine neoplasms (37) has also been shown, in vivo. In particular, differential expression of the IGF-IEc isoform was detected in PCa and prostatic intraepithelial neoplasia, as well as in bladder cancer (13, 33), compared to the corresponding normal tissues. In addition, IGF-IEc expression was found to be significantly related to TNM staging and the presence of muscular and capsule cancerous invasion in thyroid cancer, exhibiting increased levels in more aggressive compared with the non-aggressive types of cancer. Moreover, there was a positive association between the expression level of this IGF-I isoform and the risk of disease recurrence (38). Furthermore, these findings were in line with previous in vivo studies showing that IGF-IEc expression was increased in secondary compared to primary foci in neuroendocrine neoplasms (37), and that its expression was positively correlated with prostate cancer stage and Gleason's score (31). Overall, these findings imply a possible gradual increase of IGF-IEc expression during the progress of this disease.

In the present study, we did not find any association between IGF-IEc expression and overall survival of patients with RCC, nevertheless we did demonstrate that its expression is associated with clear cell RCC independently of tumor pathological stage, grade, size, and mitotic index.

Previous studies have reported that IGF-IR overexpression is associated with increased risk of death in patients with clear cell RCC compared to those who had tumors without IGF-IR expression, while the chemosensitivity of clear cell RCC cells was found to increase after silencing of IGF-IR (2, 60). However, the IGF system components have been shown to be differentially expressed among specific tumor types and particularly in clear cell RCC, where IGF-IR expression was found to be expressed in a disproportionally lower percentage of cases compared to the percentage with IGF-I expression (61), while a recent study further confirmed that the expression of IGF-IR is not related to the expression of its ligands, neither in papillary nor in clear cell RCC tumors (54). Moreover, the expression of IGF-I system components was not found be related to tumor stage, grade, or prognosis of the disease in clear cell RCC (61). Our study, for the first time, revealed a differential regulation of the specific IGF-IEc isoform among different histological types of RCC, while we found no associations of this particular component with the prognosis of the disease, specifically with the overall survival of patients with RCC.

In conclusion, the present study characterized the expression/localization of IGF-IEc isoform in human RCC tissues, showing a significantly lower expression in clear cell RCC versus all other RCC histological types. This differential expression of IGF-IEc remained significant after adjusting for other clinicopathological characteristics, such as tumor grade or stage, while it was not found to be associated with the overall survival of those patients. Further studies are needed to investigate the possible tumor type-specific regulation of the IGF-I isoforms in the pathophysiology of RCC, as previously shown in other cancer types.

Acknowledgements

The Authors recognize the invaluable contribution of the patients in use of their biopsy samples for this work.

Footnotes

  • Authors' Contributions

    FM contributed to the experimental design, carried out the experiments, analyzed data and reviewed the article; CP analyzed data and reviewed the article; AP analyzed data and wrote the article; AA analyzed data, performed the statistical analysis and reviewed the article; PM analyzed data, contributed to the statistical analysis and reviewed the article; MK conceived and designed the study, analyzed data and reviewed the article. All Authors read and approved the final version of article.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received September 17, 2020.
  • Revision received September 28, 2020.
  • Accepted September 29, 2020.
  • Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved

References

  1. ↵
    1. Semeniuk-Wojtas A,
    2. Stec Rand Szczylik C
    : Are primary renal cell carcinoma and metastases of renal cell carcinoma the same cancer? Urol Oncol 34: 215-220, 2016. PMID: 26850779. DOI: 10.1016/j.urolonc.2015.12.013
    OpenUrl
  2. ↵
    1. Tracz AF,
    2. Szczylik C,
    3. Porta C,
    4. Czarnecka AM
    : Insulin-like growth factor-1 signaling in renal cell carcinoma. BMC Cancer 16: 453, 2016. PMID: 27405474. DOI: 10.1186/s12885-016-2437-4
    OpenUrlCrossRef
  3. ↵
    1. Storkel S,
    2. van den Berg E
    : Morphological classification of renal cancer. World J Urol 13: 153-158, 1995. PMID: 7550386. DOI: 10.1007/BF00184870
    OpenUrlCrossRefPubMed
    1. Jonasch E,
    2. Gao J,
    3. Rathmell WK
    : Renal cell carcinoma. BMJ 349: g4797, 2014. PMID: 25385470. DOI: 10.1136/bmj.g4797
    OpenUrlAbstract/FREE Full Text
    1. Shuch B,
    2. Amin A,
    3. Armstrong AJ,
    4. Eble JN,
    5. Ficarra V,
    6. Lopez-Beltran A,
    7. Martignoni G,
    8. Rini BI,
    9. Kutikov A
    : Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity. Eur Urol 67: 85-97, 2015. PMID: 24857407. DOI: 10.1016/j.eururo.2014.04.029
    OpenUrlCrossRefPubMed
  4. ↵
    1. Msaouel P,
    2. Zurita AJ,
    3. Huang S,
    4. Jonasch E,
    5. Tannir NM
    : Plasma cytokine and angiogenic factors associated with prognosis and therapeutic response to sunitinib vs. everolimus in advanced non-clear cell renal cell carcinoma. Oncotarget 8: 42149-42158, 2017. PMID: 28178674. DOI: 10.18632/oncotarget.15011
    OpenUrl
  5. ↵
    1. Reyes-Moreno C,
    2. Sourla A,
    3. Choki I,
    4. Doillon C,
    5. Koutsilieris M
    : Osteoblast-derived survival factors protect PC-3 human prostate cancer cells from adriamycin apoptosis. Urology 52: 341-347, 1998. PMID: 9697810. DOI: 10.1016/s0090-4295(98)00182-4
    OpenUrlCrossRefPubMed
  6. ↵
    1. Koutsilieris M,
    2. Mitsiades C,
    3. Sourla A
    : Insulin-like growth factor I and urokinase-type plasminogen activator bioregulation system as a survival mechanism of prostate cancer cells in osteoblastic metastases: Development of anti-survival factor therapy for hormone-refractory prostate cancer. Mol Med 6: 251-267, 2000. PMID: 10949907.
    OpenUrlPubMed
    1. Mitsiades CS,
    2. Mitsiades N,
    3. Koutsilieris M
    : The AKT pathway: Molecular targets for anti-cancer drug development. Curr Cancer Drug Targets 4: 235-256, 2004. PMID: 15134532. DOI: 10.2174/1568009043333032
    OpenUrlCrossRefPubMed
  7. ↵
    1. Samani AA,
    2. Yakar S,
    3. LeRoith D,
    4. Brodt P
    : The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28: 20-47, 2007. PMID: 16931767. DOI: 10.1210/er.2006-0001
    OpenUrlCrossRefPubMed
  8. ↵
    1. Philippou A,
    2. Armakolas A,
    3. Koutsilieris M
    : Evidence for the possible biological significance of the IGF-1 gene alternative splicing in prostate cancer. Front Endocrinol 4: 31, 2013. PMID: 23519101. DOI: 10.3389/fendo.2013.00031
    OpenUrl
    1. Philippou A,
    2. Christopoulos PF,
    3. Koutsilieris M
    : Clinical studies in humans targeting the various components of the IGF system show lack of efficacy in the treatment of cancer. Mutat Res Rev Mutat Res 772: 105-122, 2016. PMID: 28528684. DOI: 10.1016/j.mrrev.2016.09.005
    OpenUrl
  9. ↵
    1. Mourmouras N,
    2. Philippou A,
    3. Christopoulos P,
    4. Kostoglou K,
    5. Grivaki C,
    6. Konstantinidis C,
    7. Serafetinides E,
    8. Delakas D,
    9. Koutsilieris M
    : Differential expression of IGF-I transcripts in bladder cancer. Anticancer Res 38: 3453-3459, 2018. PMID: 29848696. DOI: 10.21873/anticanres.12614
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Gkioka E,
    2. Msaouel P,
    3. Philippou A,
    4. Vlaghogiannis NI,
    5. Vogkou CT,
    6. Margiolis A,
    7. Koutsilieris M
    : Review: The role of insulin-like growth factor-1 signaling pathways in uterine leiomyoma. In Vivo 29: 637-649, 2015. PMID: 26546520.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Solarek W,
    2. Czarnecka AM,
    3. Escudier B,
    4. Bielecka ZF,
    5. Lian F,
    6. Szczylik C
    : Insulin and IGFs in renal cancer risk and progression. Endocr Relat Cancer 22: R253-264, 2015. PMID: 26330483. DOI: 10.1530/ERC-15-0135
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Cao Q,
    2. Liang C,
    3. Xue J,
    4. Li P,
    5. Li J,
    6. Wang M,
    7. Zhang Z,
    8. Qin C,
    9. Lu Q,
    10. Hua L,
    11. Shao P,
    12. Wang Z
    : Genetic variation in IGF1 predicts renal cell carcinoma susceptibility and prognosis in Chinese population. Sci Rep 6: 39014, 2016. PMID: 27976731. DOI: 10.1038/srep39014
    OpenUrl
  13. ↵
    1. Moschos MM,
    2. Armakolas A,
    3. Philippou A,
    4. Pissimissis N,
    5. Panteleakou Z,
    6. Nezos A,
    7. Kaparelou M,
    8. Koutsilieris M
    : Expression of the insulin-like growth factor 1 (IGF-1) and type I IGF receptor mRNAs in human HLE-B3 lens epithelial cells. In Vivo 25: 179-184, 2011. PMID: 21471532.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Milingos DS,
    2. Philippou A,
    3. Armakolas A,
    4. Papageorgiou E,
    5. Sourla A,
    6. Protopapas A,
    7. Liapi A,
    8. Antsaklis A,
    9. Mastrominas M,
    10. Koutsilieris M
    : Insulin-like growth factor-1Ec (MGF) expression in eutopic and ectopic endometrium: Characterization of the MGF E-peptide actions in vitro. Mol Med 17: 21-28, 2011. PMID: 20844834. DOI: 10.2119/molmed.2010.00043
    OpenUrlCrossRefPubMed
    1. Stavropoulou A,
    2. Halapas A,
    3. Sourla A,
    4. Philippou A,
    5. Papageorgiou E,
    6. Papalois A,
    7. Koutsilieris M
    : IGF-1 expression in infarcted myocardium and MGF E peptide actions in rat cardiomyocytes in vitro. Mol Med 15: 127-135, 2009. PMID: 19295919. DOI: 10.2119/molmed.2009.00012
    OpenUrlPubMed
  15. ↵
    1. Philippou A,
    2. Papageorgiou E,
    3. Bogdanis G,
    4. Halapas A,
    5. Sourla A,
    6. Maridaki M,
    7. Pissimissis N,
    8. Koutsilieris M
    : Expression of IGF-1 isoforms after exercise-induced muscle damage in humans: Characterization of the MGF E peptide actions in vitro. In Vivo 23: 567-575, 2009. PMID: 19567392.
    OpenUrlAbstract/FREE Full Text
    1. Philippou A,
    2. Barton ER
    : Optimizing IGF-I for skeletal muscle therapeutics. Growth Horm IGF Res 24: 157-163, 2014. PMID: 25002025. DOI: 10.1016/j.ghir.2014.06.003
    OpenUrl
    1. Barton ER,
    2. Park S,
    3. James JK,
    4. Makarewich CA,
    5. Philippou A,
    6. Eletto D,
    7. Lei H,
    8. Brisson B,
    9. Ostrovsky O,
    10. Li Z,
    11. Argon Y
    : Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production. FASEB J 26: 3691-3702, 2012. PMID: 22649033. DOI: 10.1096/fj.11-203026
    OpenUrlCrossRefPubMed
    1. Durzynska J,
    2. Philippou A,
    3. Brisson BK,
    4. Nguyen-McCarty M,
    5. Barton ER
    : The pro-forms of insulin-like growth factor I (IGF-I) are predominant in skeletal muscle and alter IGF-I receptor activation. Endocrinology 154: 1215-1224, 2013. PMID: 23407451. DOI: 10.1210/en.2012-1992
    OpenUrlCrossRefPubMed
  16. ↵
    1. Philippou A,
    2. Maridaki M,
    3. Pneumaticos S,
    4. Koutsilieris M
    : The complexity of the IGF1 gene splicing, posttranslational modification and bioactivity. Mol Med 20: 202-214, 2014. PMID: 24637928. DOI: 10.2119/molmed.2014.00011
    OpenUrlPubMed
  17. ↵
    1. Thomas CG,
    2. Psarros C,
    3. Gekas A,
    4. Vandoros GP,
    5. Philippou A,
    6. Koutsilieris M
    : Alternative splicing of IGF1 gene as a potential factor in the pathogenesis of Peyronie's disease. In Vivo 30: 251-256, 2016. PMID: 27107083.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Philippou A,
    2. Maridaki M,
    3. Halapas A,
    4. Koutsilieris M
    : The role of the insulin-like growth factor 1 (IGF-1) in skeletal muscle physiology. In Vivo 21: 45-54, 2007. PMID: 17354613.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Bikle DD,
    2. Tahimic C,
    3. Chang W,
    4. Wang Y,
    5. Philippou A,
    6. Barton ER
    : Role of IGF-I signaling in muscle bone interactions. Bone 80: 79-88, 2015. PMID: 26453498. DOI: 10.1016/j.bone.2015.04.036
    OpenUrl
  20. ↵
    1. Philippou A,
    2. Halapas A,
    3. Maridaki M,
    4. Koutsilieris M
    : Type I insulin-like growth factor receptor signaling in skeletal muscle regeneration and hypertrophy. J Musculoskelet Neuronal Interact 7: 208-218, 2007. PMID: 17947802.
    OpenUrlPubMed
  21. ↵
    1. Nagel JM,
    2. Geiger BM,
    3. Karagiannis AK,
    4. Gras-Miralles B,
    5. Horst D,
    6. Najarian RM,
    7. Ziogas DC,
    8. Chen X,
    9. Kokkotou E
    : Reduced intestinal tumorigenesis in APCmin mice lacking melanin-concentrating hormone. PLoS One 7: e41914, 2012. PMID: 22848656. DOI: 10.1371/journal.pone.0041914
    OpenUrlPubMed
  22. ↵
    1. Hakam A,
    2. Yeatman TJ,
    3. Lu L,
    4. Mora L,
    5. Marcet G,
    6. Nicosia SV,
    7. Karl RC,
    8. Coppola D
    : Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol 30: 1128-1133, 1999. PMID: 10534157. DOI: 10.1016/s0046-8177(99)90027-8
    OpenUrlCrossRefPubMed
  23. ↵
    1. Savvani A,
    2. Petraki C,
    3. Msaouel P,
    4. Diamanti E,
    5. Xoxakos I,
    6. Koutsilieris M
    : IGF-IEc expression is associated with advanced clinical and pathological stage of prostate cancer. Anticancer Res 33: 2441-2445, 2013. PMID: 23749893.
    OpenUrlAbstract/FREE Full Text
    1. Koutsilieris M,
    2. Polychronakos C
    : Proteinolytic activity against IGF-binding proteins involved in the paracrine interactions between prostate adenocarcinoma cells and osteoblasts. Anticancer Res 12: 905-910, 1992. PMID: 1377896.
    OpenUrlPubMed
  24. ↵
    1. Armakolas A,
    2. Philippou A,
    3. Panteleakou Z,
    4. Nezos A,
    5. Sourla A,
    6. Petraki C,
    7. Koutsilieris M
    : Preferential expression of IGF-1Ec (MGF) transcript in cancerous tissues of human prostate: evidence for a novel and autonomous growth factor activity of MGF E peptide in human prostate cancer cells. Prostate 70: 1233-1242, 2010. PMID: 20564425 DOI: 10.1002/pros.21158
    OpenUrlCrossRefPubMed
  25. ↵
    1. Philippou A,
    2. Armakolas A,
    3. Panteleakou Z,
    4. Pissimissis N,
    5. Nezos A,
    6. Theos A,
    7. Kaparelou M,
    8. Armakolas N,
    9. Pneumaticos SG,
    10. Koutsilieris M
    : IGF1Ec expression in MG-63 human osteoblast-like osteosarcoma cells. Anticancer Res 31: 4259-4265, 2011. PMID: 22199289.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Christopoulos PF,
    2. Papageorgiou E,
    3. Petraki C,
    4. Koutsilieris M
    : The COOH-terminus of the IGF-1Ec isoform enhances the proliferation and migration of human MCF-7 Breast Cancer Cells. Anticancer Res 37: 2899-2912, 2017. PMID: 28551627. DOI: 10.21873/anticanres.11643
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Brodt P,
    2. Fallavollita L,
    3. Khatib AM,
    4. Samani AA,
    5. Zhang D
    : Cooperative regulation of the invasive and metastatic phenotypes by different domains of the type I insulin-like growth factor receptor beta subunit. J Biol Chem 276: 33608-33615, 2001. PMID: 11445567. DOI: 10.1074/jbc.M102754200
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Alexandraki KI,
    2. Philippou A,
    3. Boutzios G,
    4. Theohari I,
    5. Koutsilieris M,
    6. Delladetsima IK,
    7. Kaltsas GA
    : IGF-IEc expression is increased in secondary compared to primary foci in neuroendocrine neoplasms. Oncotarget 8: 79003-79011, 2017. PMID: 29108282. DOI: 10.18632/oncotarget.20743
    OpenUrl
  29. ↵
    1. Karagiannis AK,
    2. Philippou A,
    3. Tseleni-Balafouta S,
    4. Zevolis E,
    5. Nakouti T,
    6. Tsopanomichalou-Gklotsou M,
    7. Psarras V,
    8. Koutsilieris M
    : IGF-IEc expression is associated with advanced differentiated thyroid cancer. Anticancer Res 39: 2811-2819, 2019. PMID: 31177118. DOI: 10.21873/anticanres.13409
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Shigematsu S,
    2. Yamauchi K,
    3. Nakajima K,
    4. Iijima S,
    5. Aizawa T,
    6. Hashizume K
    : IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocr J 46 Suppl: S59-62, 1999. PMID: 12054122. DOI: 10.1507/endocrj.46.suppl_s59
    OpenUrlCrossRefPubMed
  31. ↵
    1. Vassilakos G,
    2. Philippou A,
    3. Koutsilieris M
    : Identification of the IGF-1 processing product human Ec/rodent Eb peptide in various tissues: Evidence for its differential regulation after exercise-induced muscle damage in humans. Growth Horm IGF Res 32: 22-28, 2017. PMID: 27836414. DOI: 10.1016/j.ghir.2016.11.001
    OpenUrl
  32. ↵
    1. Christopoulos PF,
    2. Philippou A,
    3. Koutsilieris M
    : Pattern of IGF-1 variant expression in human cancer cell lines using a novel q-RT-PCR approach. Anticancer Res 35: 107-115, 2015. PMID: 25550540.
    OpenUrlAbstract/FREE Full Text
    1. Kasprzak A,
    2. Szaflarski W,
    3. Szmeja J,
    4. Andrzejewska M,
    5. Przybyszewska W,
    6. Kaczmarek E,
    7. Koczorowska M,
    8. Kościński T,
    9. Zabel M,
    10. Drews M
    : Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue. Int J Oncol 42: 305-316, 2012. PMID: 23165777. DOI: 10.3892/ijo.2012.1706
    OpenUrl
  33. ↵
    1. Christopoulos PF,
    2. Msaouel P,
    3. Koutsilieris M
    : The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer 14: 43, 2015. PMID: 25743390. DOI: 10.1186/s12943-015-0291-7
    OpenUrlCrossRefPubMed
  34. ↵
    1. Papageorgiou E,
    2. Philippou A,
    3. Armakolas A,
    4. Christopoulos PF,
    5. Dimakakos A,
    6. Koutsilieris M
    : The human Ec peptide: The active core of a progression growth factor with species-specific mode of action. Hormones 15: 423-434, 2016. PMID: 27838607. DOI: 10.14310/horm.2002.1699
    OpenUrl
  35. ↵
    1. Vassilakos G,
    2. Philippou A,
    3. Tsakiroglou P,
    4. Koutsilieris M
    : Biological activity of the e domain of the IGF-1Ec as addressed by synthetic peptides. Hormones 13: 182-196, 2014. PMID: 24776619. DOI: 10.1007/BF03401333
    OpenUrl
  36. ↵
    1. Armakolas A,
    2. Kaparelou M,
    3. Dimakakos A,
    4. Papageorgiou E,
    5. Armakolas N,
    6. Antonopoulos A,
    7. Petraki C,
    8. Lekarakou M,
    9. Lelovas P,
    10. Stathaki M,
    11. Psarros C,
    12. Donta I,
    13. Galanos PS,
    14. Msaouel P,
    15. Gorgoulis VG,
    16. Koutsilieris M
    : Oncogenic role of the Ec peptide of the IGF-1Ec isoform in prostate cancer. Mol Med 21: 167-179, 2015. PMID: 25569803. DOI: 10.2119/molmed.2014.00222
    OpenUrlCrossRefPubMed
  37. ↵
    1. Moch H,
    2. Cubilla AL,
    3. Humphrey PA,
    4. Reuter VE,
    5. Ulbright TM
    : The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: Renal, penile, and testicular tumours. Eur Urol 70(1): 93-105, 2016. PMID: 26935559 DOI: 10.1016/j.eururo.2016.02.029
    OpenUrlCrossRefPubMed
  38. ↵
    1. Philippou A,
    2. Stavropoulou A,
    3. Sourla A,
    4. Pissimissis N,
    5. Halapas A,
    6. Maridaki M,
    7. Koutsilieris M
    : Characterization of a rabbit antihuman mechano growth factor (MGF) polyclonal antibody against the last 24 amino acids of the E domain. In Vivo 22: 27-35, 2008. PMID: 18396778.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Fine JP,
    2. Gray RJ
    : A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94: 496–509, 1999. DOI: 10.2307/2670170
    OpenUrlCrossRef
  40. ↵
    1. Singh P,
    2. Dai B,
    3. Yallampalli U,
    4. Lu X,
    5. Schroy PC
    : Proliferation and differentiation of a human colon cancer cell line (CaCo2) is associated with significant changes in the expression and secretion of insulin-like growth factor (IGF) IGF-II and IGF binding protein-4: Role of IGF-II. Endocrinology 137: 1764-1774, 1996. PMID: 8612513. DOI: 10.1210/endo.137.5.8612513
    OpenUrlCrossRefPubMed
    1. LeRoith D,
    2. Baserga R,
    3. Helman L,
    4. Roberts CT Jr.
    : Insulin-like growth factors and cancer. Ann Intern Med 122: 54-59, 1995. PMID: 7619109. DOI: 10.7326/0003-4819-122-1-199501010-00009
    OpenUrlCrossRefPubMed
    1. Yaginuma Y,
    2. Nishiwaki K,
    3. Kitamura S,
    4. Hayashi H,
    5. Sengoku K,
    6. Ishikawa M
    : Relaxation of insulin-like growth factor-II gene imprinting in human gynecologic tumors. Oncology 54: 502-507, 1997. PMID: 9394848. DOI: 10.1159/000227610
    OpenUrlPubMed
  41. ↵
    1. Frostad S,
    2. Bruserud O
    : aIn vitro effects of insulin-like growth factor-1 (IGF-1) on proliferation and constitutive cytokine secretion by acute myelogenous leukemia blasts. Eur J Haematol 62: 191-198, 1999. PMID: 10089897. DOI: 10.1111/j.1600-0609.1999.tb01743.x
    OpenUrlPubMed
  42. ↵
    1. Solarek W,
    2. Koper M,
    3. Lewicki S,
    4. Szczylik C,
    5. Czarnecka AM
    : Insulin and insulin-like growth factors act as renal cell cancer intratumoral regulators. J Cell Commun Signal 13: 381-394, 2019. PMID: 30929166. DOI: 10.1007/s12079-019-00512-y
    OpenUrlCrossRef
    1. Xu J,
    2. Chang WH,
    3. Fong LWR,
    4. Weiss RH,
    5. Yu SL,
    6. Chen CH
    : Targeting the insulin-like growth factor-1 receptor in MTAP-deficient renal cell carcinoma. Signal Transduct Target Ther 4: 2, 2019. PID: 30701095. DOI: 10.1038/s41392-019-0035-z
    OpenUrl
  43. ↵
    1. Cheung CW,
    2. Vesey DA,
    3. Nicol DL,
    4. Johnson DW
    : The roles of IGF-I and IGFBP-3 in the regulation of proximal tubule, and renal cell carcinoma cell proliferation. Kidney Int 65: 1272-1279, 2004. PMID: 15086466. DOI: 10.1111/j.1523-1755.2004.00535.x
    OpenUrlCrossRefPubMed
  44. ↵
    1. Armakolas N,
    2. Armakolas A,
    3. Antonopoulos A,
    4. Dimakakos A,
    5. Stathaki M,
    6. Koutsilieris M
    : The role of the IGF-1 Ec in myoskeletal system and osteosarcoma pathophysiology. Crit Rev Oncol Hematol 108: 137-145, 2016. PMID: 27931832. DOI: 10.1016/j.critrevonc.2016.11.004
    OpenUrlCrossRefPubMed
  45. ↵
    1. Armakolas N,
    2. Dimakakos A,
    3. Armakolas A,
    4. Antonopoulos A,
    5. Koutsilieris M
    : Possible role of the Ec peptide of IGF1Ec in cartilage repair. Mol Med Rep 14: 3066-3072, 2016. PMID: 27571686. DOI: 10.3892/mmr.2016.5627
    OpenUrl
  46. ↵
    1. Armakolas A,
    2. Dimakakos A,
    3. Loukogiannaki C,
    4. Armakolas N,
    5. Antonopoulos A,
    6. Florou C,
    7. Tsioli P,
    8. Papageorgiou P,
    9. Alexandrou TP,
    10. Stathaki M,
    11. Spinos D,
    12. Pektasides D,
    13. Patsouris E,
    14. Koutsilieris Ml
    : IL-6 is associated with IGF-1Ec up-regulation and Ec peptide secretion, from prostate tumors. Mol Med 24: 6, 2018. PMID: 30134795. DOI: 10.1186/s10020-018-0003-z
    OpenUrl
  47. ↵
    1. Parker A,
    2. Cheville JC,
    3. Lohse C,
    4. Cerhan JR,
    5. Blute ML
    : Expression of insulin-like growth factor I receptor and survival in patients with clear cell renal cell carcinoma. J Urol 170: 420-424, 2003. PMID: 12853790. DOI: 10.1097/01.ju.0000071474.70103.92
    OpenUrlCrossRefPubMed
  48. ↵
    1. Schips L,
    2. Zigeuner R,
    3. Ratschek M,
    4. Rehak P,
    5. Ruschoff J,
    6. Langner C
    : Analysis of insulin-like growth factors and insulin-like growth factor I receptor expression in renal cell carcinoma. Am J Clin Pathol 122: 931-937, 2004. PMID: 15539386. DOI: 10.1309/G7PY-0RE7-T86H-HQYV
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Anticancer Research: 40 (11)
Anticancer Research
Vol. 40, Issue 11
November 2020
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
  • Back Matter (PDF)
  • Ed Board (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on Anticancer Research.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Expression of IGF-IEc Isoform in Renal Cell Carcinoma Tissues
(Your Name) has sent you a message from Anticancer Research
(Your Name) thought you would like to see the Anticancer Research web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
1 + 18 =
Solve this simple math problem and enter the result. E.g. for 1+3, enter 4.
Citation Tools
Expression of IGF-IEc Isoform in Renal Cell Carcinoma Tissues
FANI MICHALOPOULOU, CONSTANTINA PETRAKI, ANASTASSIOS PHILIPPOU, ANTONIS ANALITIS, PAVLOS MSAOUEL, MICHAEL KOUTSILIERIS
Anticancer Research Nov 2020, 40 (11) 6213-6219; DOI: 10.21873/anticanres.14641

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Reprints and Permissions
Share
Expression of IGF-IEc Isoform in Renal Cell Carcinoma Tissues
FANI MICHALOPOULOU, CONSTANTINA PETRAKI, ANASTASSIOS PHILIPPOU, ANTONIS ANALITIS, PAVLOS MSAOUEL, MICHAEL KOUTSILIERIS
Anticancer Research Nov 2020, 40 (11) 6213-6219; DOI: 10.21873/anticanres.14641
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgements
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • TIG1 Inhibits the mTOR Signaling Pathway in Malignant Melanoma Through the VAC14 Protein
  • Novel α-Trifluoromethyl Chalcone Exerts Antitumor Effects Against Prostate Cancer Cells
  • Differential Effects of Anti-PD-1/PD-L1 Checkpoint Inhibitors on Adhesion Molecules and Cytokine Secretion by THP-1 Monocytes
Show more Experimental Studies

Similar Articles

Keywords

  • Insulin-like growth factor-I
  • IGF-I
  • IGF-IEc
  • Renal cancer
  • clear cell RCC
Anticancer Research

© 2023 Anticancer Research

Powered by HighWire