Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

  • Authors:
    • Jingsheng Yuan
    • Zhijie Yin
    • Kaixiong Tao
    • Guobing Wang
    • Jinbo Gao
  • View Affiliations

  • Published online on: October 26, 2017     https://doi.org/10.3892/ol.2017.7276
  • Pages: 41-47
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Drug resistance is a primary cause of chemo­therapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin‑like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R‑induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP‑binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options.

Introduction

Insulin-like growth factor 1 receptor (IGF1R) signaling is a complicated and regulated network essential for cells to proliferate and survive. The IGF-IGF1R axis consists of three receptor tyrosine kinases: IGF1R, insulin-like growth factor-2 receptor (IGF2R) and insulin receptor (INSR). The ligands for these receptors are insulin, insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2) and serum insulin-like growth factor binding proteins (IGFBPs) (1). IGF-1 and IGF-2 possess autocrine, paracrine and endocrine functions, and activate IGF1R signaling (2). These growth factors and their receptors are commonly overexpressed in malignant tumors; this overexpression may be used to assess cancer through sustained proliferative signals, anti-apoptotic events, invasion, metastasis and drug resistance in cancer cells (3).

IGF1R expression and activity increases in numerous tumor types, including ovarian cancer and rhabdomyosarcoma, and is reported to contribute to cancer cell proliferation and apoptosis (4,5). Since IGF1R functions as a membrane receptor, drugs, including IGF1R tyrosine kinase inhibitors, monoclonal antibodies against IGF1R and monoclonal antibodies against IGF1R ligands targeting this receptor, are of particular interest (6). Recently, the function of IGF1R in chemotherapeutic resistance has gained increasing attention, and relevant mechanisms of inducing resistance in cancer cells include overexpressing multi-drug-resistant proteins, dysregulating cell survival and death and interacting with the tumor microenvironment (7).

IGF1R signaling pathway

IGF1R structure and function

IGF1R is an insulin receptor family member, and a disulfide-linked heterotetrameric transmembrane glycoprotein (αββα) that contains an extracellular ligand-binding domain and an intracellular tyrosine kinase domain (8,9). The ligand-binding specificity determinant is reflected in the amino-terminal cysteine-rich domain of the extracellular α subunit, primarily recognizing and binding to IGF-1 and IGF-2. The intracellular signal transduction depends on the tyrosine kinase activity the ligand in the transmembrane β subunit triggers, permitting specific insulin receptor substrates (IRS-1 to −4) and Src-homology collagen (Shc) to phosphorylate, activating downstream mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways (6). The specificity of IGF1R in vivo depends on tissue distribution, ligand-binding specificity and receptor differences in intrinsic signaling (10).

IGF1R is often expressed in normal tissues, serving multiple physiological functions in growth, development and feeding (11). The importance of IGF1R in prenatal and postnatal growth has been demonstrated using knockout mice (8). In muscle and bone tissues, IGF1R signaling promotes PI3K/AKT-mediated differentiation and extracellular signal-regulated kinase (ERK) (12). IGF1R also aids in the maintenance of the myocardium and brain (13).

Cardiac-specific IGF1R signaling promotes protective physiological hypertrophy, preserving left ventricular function and inhibiting pathological left ventricular remodeling (14). Furthermore, IGF1R contributes to glucose metabolism and neutrophil physiology (15), and is associated with the occurrence and development of cardiovascular disease, diabetes and inflammation (16,17).

IGF1R is commonly overexpressed in cancer (18). The IGF1R signal promotes non-cancerous cells to malignantly transform (19), and possesses anti-apoptotic and mitogenic activity (2022). In addition, IGF1R contributes to invasion, metastasis and angiogenesis of cancer (2325). Excessively activating IGF1R promotes tumors to progress by increasing glycolysis and biomass production (26), and decreases tumor sensitivity to hypoxia, low pH and low glucose environments (27). In addition, expressing IGF1R increases the rate at which tumor cells proliferate and decreases the rate at which they are destroyed (28).

IGF1R gene regulation

The 5′-flanking region promoter of IGF1R is enriched in GC, and lacks the effective transcription initiation of the majority of eukaryotic genes usually requiring TATA and CCAAT boxes. This characteristic results in a partial difference in its gene regulation compared with other promoter regions (29,30).

IGF1R gene expression is regulated transcriptionally and post-transcriptionally

Previous studies have suggested that numerous transcription factors regulate the IGF1R gene. Transactivation factors include zinc finger protein specificity protein 1 (Sp1), forkhead box protein O3 (Foxo3), E2F1 transcription factor, Krüppel-like factor 6, EWS RNA binding protein 1-Wilms tumor 1 (WT1) fusion protein and high mobility group A1, all of which bind directly to the IGF1R promoter (3134). In contrast, estrogen, BRCA1 DNA repair associated (BRCA1) and von Hippel-Lindau tumor suppressor inhibit IGF1R expression by binding to Sp1 (31,35). A previous study confirmed that WT1 specifically binds to co-WT1 cis-elements in the IGF1R proximal promoter region, and decreases IGF1R gene transcription and translation (36). Overexpressing MYB proto-oncogene transcription factor in tumor cells increases the expression of IGF-1 and IGF1R by increasing transcriptional activity (37).

IGF1R-associated signaling pathways

IGF1R is associated with multiple signaling pathways via downstream proteins, including IRS and PI3K (3840). IGF1R, which mediates apoptosis-inhibiting signals, and enhances cell metabolism and protein synthesis via downstream mechanistic target of rapamycin (MTOR) kinase signaling, activates the PI3K/AKT signaling pathway (4143). IGF1R activates the growth factor receptor bound protein 2 (Grb2)/RAS/RAF/MAPK signaling pathway to transduce cell growth and proliferation signals (44,45). IGF1R activation or overexpression is associated with invasion and metastasis of cancer cells, processes mediated by numerous signal transduction proteins that affect invasiveness (24,25). For example, phosphorylating IRS-1 affects the interactions between epithelial cadherin and β-catenin, and the crosstalk between the IGF axis and integrins (46). A previous study demonstrated that protein tyrosine kinase 6 forms a complex with IGF1R and the adaptor protein IRS-1, which modulates anchorage-independent growth via the regulation of IGF1R expression and phosphorylation (23).

Previously, crosstalk between IGF1R and other signaling pathways has been assessed, with studies focusing on interactions between IGF1R, steroid hormones and other receptor tyrosine kinases (RTKs) (47). The crosstalk between IGF1R and focal adhesion kinase (FAK) signaling pathways (38), IGF1R and the classical Wnt signaling pathways (48,49), and IGF1R and transforming growth factor β (TGFβ) signaling pathways have also been further clarified (50). In addition, certain IGF1R signals have been newly identified, namely RTK heterodimers, including the INSR hybrid receptor, and IGF1R/INSR that function as dependent receptors intervening in IGF1R signaling and its regulation (51).

The IGF1R signaling pathway is regulated at multiple levels; the expression of IGF-2, the presence of IGF2R and high-affinity IGFBPs affects ligand-binding activity (52). In addition, other extracellular factors, including dendritic cells and integrins, may contribute to regulating IGF1R activity (53). Within cells, Notch and apoptosis inducing factor-1 regulates IGF1R kinase activity (54). Downstream, multiple IGF1R effectors participate in IRS/PI3K/AKT signal transmission, including MTOR complex 1, phosphatase and tensin homolog phosphohydrolase, ribosomal protein S6 kinases, ERK and c-Jun N-terminal kinase (5,55,56).

IGF1R and chemotherapy resistance

Overexpression of IGF1R is associated with poorer chemotherapy outcomes for patients with gastric cancer compared with those with low expression of IGF1R (57). Patients with co-expression of IGF1R and multi-drug resistance-associated protein 1 (MRP1) have demonstrated a poorer response with adjuvant FOLFOX-4 chemotherapy (58). In patients with human epidermal growth factor receptor 2-negative breast cancer, the decreased expression of IGF1R was correlated with an improved response to chemotherapy (59). Blocking IGF1R signaling facilitates treating bladder cancer cells that are insensitive to chemotherapy (60). Similar phenomena have been reported for prostate and ovarian cancer when IGF1R signaling is blocked (61,62). Although the function of IGF1R in chemotherapy resistance has been confirmed, the mechanism remains to be fully elucidated. The present study assessed IGF1R-associated tolerance mechanisms from multiple aspects, including promoting proliferation, inhibiting apoptosis, and inducing changes to ATP-binding cassette (ABC) transporter proteins and the extracellular matrix (ECM) (Fig. 1).

Promoting proliferation

A characteristic of tumor cells, persistent proliferation may be acquired in multiple ways (3). As chemotherapeutic resistance develops, certain signals elevate receptor proteins on tumor cell surfaces and permit cells to avoid growth signal control (57). Changing the receptor's molecular structure, which alters ligand restriction and promotes the downstream signal to activate, may achieve the same effect (63).

The Grb2/RAS/RAF/MAPK cascades serve crucial functions in cell proliferation and survival and are aberrantly activated in drug-tolerant cells. Numerous mechanisms increase IGF1R expression and activate IGF1R, thereby promoting signaling cascades and proliferation (64). WT1 is reportedly silenced in drug-resistant cells, which may degrade the inhibitory effect of WT1 on IGF1R transcription (65). Similar effects are reflected in the feedback loop between Foxo3, IGF1R and AKT (31). Micro (mi) RNA inhibits IGF1R expression by directly targeting the 3′ untranslated regions but CpG methylating the miRNA promoter region results in the downregulation, and the loss of the inhibitory effects, of IGF1R expression (66,67). MIR-143, MIR-503 and MIR-1271 regulate cisplatin resistance in human gastric cancer cell lines by targeting IGF1R (6669). Normally, insulin-like growth factor binding protein-7 (IGFBP7) directly binds to IGF1R and inhibits its function post-transcriptionally; however, studies indicate that, in chemotherapy-resistant cells, IGFBP7 expression significantly decreased (70). Therefore, IGF1R is overactivated once IGFBP7 inhibitory activity has decreased (71). Furthermore, inactivating IGF1R inhibits tumor cell proliferation by blockading G0/G1 and IGF1R binds to non-IGF ligands from extracellular spaces, cell membranes and the cytoplasm, which regulates cell proliferation and survival IGF-independently during chemoresistance (72,73).

In addition to overexpression, IGF1R over-activation is also important with respect to chemotherapeutic tolerance. Phosphorylated IGF1R increased in chemotherapeutic drug-resistant cell lines (7476) and multiple mechanisms contribute to the over-activation of IGF1R, including increased constitutively secreted IGF-1 (63), transgelin overexpression (77) and the effect of the Src oncogene on IGF1R (78). By these processes, IGF1R signals promote tumor cells to proliferate and induce resistance by over-activating Grb2/RAS/RAF/MAPK cascades (64).

Inhibiting apoptosis

Anti-apoptosis is common to numerous tumors and chemotherapy-resistant cells evolve diverse strategies to limit or avoid apoptosis (3). The most common strategy is to eliminate the tumor suppressor function of p53 (79). Resistant cells also downregulate pro-apoptotic factors or increase the expression of anti-apoptotic factors to avoid apoptosis (80). IGF1R participates in apoptosis inhibition predominantly via the PI3K/AKT signaling pathway in drug-resistant cell lines but multiple other mechanisms are associated with IGF1R overexpression and inhibition of apoptosis in drug-resistant cells (81,82).

Previous studies have indicated that cancer chemotherapy is associated with inducing p53-dependent apoptosis responses (79). p53 is one of the most frequently mutated tumor suppressors and IGF1R overexpression inhibits wild-type p53 (WT-p53) via phosphorylated (p) AKT (80). This enhances the ubiquitination-promoting function of murine double minute 2, which decreases p53 protein production (79). Reciprocally, WT-p53 renders tumor cells more chemosensitive by inhibiting Sp1-induced transactivation of the IGF1R promoter and increasing the expression of pro-apoptotic protein p21 (81). Mutant p53 stimulates IGF1R promoter function in chemotherapeutic resistant cell lines (82). Furthermore, IGF1R regulates cisplatin resistance by targeting proto-oncogene Bcl-2, which is anti-apoptotic and affects drug resistance by binding to and inhibiting Bcl 2-associated X protein (BAX) and Bcl 2 homologous antagonist killer protein (83). IGF1R activation is also associated with decreased expression of IGFBP7, which is associated with the expression of the anti-apoptotic gene Bim and chemotherapy tolerance-associated genes, including annexin A4 and protein kinase C 1 (84). Conversely, overexpressing IGFBP7 induces apoptosis and reverses tumor drug resistance (70).

Regulating ABC transporter proteins

The ABC is the largest protein transporter superfamily present in all organisms (85). This family of genes codes for different proteins (importers and exporters) and its increased expression decreases drug influx and increases efflux, decreasing therapeutic response (86). IGF1R signals participate in regulating ABC genes, including multidrug resistance protein 1 (MDR1), MRP1, multidrug resistance-associated protein 2 (MRP2), multidrug resistance-associated protein 3 (MRP3) and breast cancer resistance protein (BCRP) (59,8789). As such, IGF1R increases tumor resistance by increasing the expression of MDR1, a protein implicated in chemotherapeutic resistance (88). Expression of MRP3 and BCRP decreases or disappears in the presence of an IGF1R inhibitor (87) and overexpressing IGF1R results in increased MRP2 promoter activity via increased pAKT and nuclear factor erythroid 2-related factor 2 in resistant cells (59,88). In addition, IGF1R silencing increases chemotherapeutic sensitivity via transcription inhibition of MRP-2 (59). Previous studies have demonstrated that overexpressing IGF1R and MRP1 was associated with chemotherapeutic resistance and poorer prognosis compared with malignancies with normal or low expression of IGF1R and MRP1, indicating that the co-expression of IGF1R/MRP1 in tumors may predict chemotherapeutic effects (88,89).

Interacting with ECM

The ECM is predominantly composed of fibrin (collagen and laminin) and proteoglycans (hyaluronic acid), which forms the structural framework for the majority of tissues (90). The ECM transfer signals to the cells via integrin binding and activation, which modulate cell proliferation, survival and migration and influence the tumor response to anti-cancer therapies (91,92).

Previous studies have indicated that IGF1R stabilizes the molecular structure of β1 integrin by protecting it from proteasomal degradation and promoting tumor cells to grow and proliferate (93). FAK, a substrate protein of IGF1R, is activated by integrin, affecting epithelial transformation, invasion and metastasis of tumor cells IGF1R-independently (38). Extracellular fibronectin increases the activity of β1 integrin to increase the abundance of MAPK-phosphatase-1 and the receptor of activated C kinase (RACK-1) (62). In addition, establishing crosstalk between β1 integrin and IGF1R retains the phosphorylation of IGF1R, which helps stimulate downstream signaling of IGF1R, and contributes to cell proliferation and transformation (94). Previous studies have revealed that, in the presence of IGF1R, the β1 integrin receptor increased the recruitment of RACK-1 and mediated tumor cell migration (62). These changes contribute to chemotherapeutic tolerance.

Other mechanisms

Previous studies have revealed that IGF1R is sumoylated and translocated to the nucleus, which permits the receptor to interact with chromatin, and function as a transcriptional regulator (9597). Nuclear IGF1R specifically binds to and functions as a transcriptional activator of its own promoter, and interferes with signaling pathways (98). Specifically, nuclear IGF1R interferes with Wnt signaling, which upregulates ABC drug transporters and modulates drug responses (99). Regarding the tumor microenvironment, activating IGF1R results in stabilizing hypoxia-inducible factor (HIF)-1α and HIF-2α, and the upregulation of vascular endothelial growth factor (100). A previous study demonstrated that overexpressing HIF-1α increased the expression of Bcl-2, decreased the expression of BAX, and induced the expression of MDR1 and MRP1 (101). These results offer novel insights into IGF1R-mediated chemotherapeutic resistance.

Conclusions

Chemotherapeutic resistance commonly results in cancer treatment failing, with previous studies confirming multiple resistance-associated mechanisms (102,103). Therefore, understanding how tumors develop resistance may help to identify improved drugs and increase patient survival rates.

Changes in drug transporter proteins, activating signaling pathways and ineffectively inducing cell death are primary mechanisms of chemotherapeutic resistance. IGF1R-mediated resistance includes promoting cells to proliferate, inhibiting apoptosis, inducing increased expression of ABC transporter proteins on cell membranes and inducing changes in the ECM. Transcription factors and miRNAs also intervene in regulating IGF1R transcriptionally and cause downstream signaling pathways to excessively activate by promoting increased IGF1R expression or loss of inhibitory effects to the IGF1R promoter. IGFBPs participate in regulating IGF1R post-transcriptionally, with the loss of IGF1R inhibition and enhanced expression of anti-apoptotic and chemotherapy resistance-associated genes. Following overexpression and over-activation, IGF1R predominantly triggers the Grb2/RAS/RAF/MAPK and PI3K/AKT cascades, which induce proliferation and inhibit apoptosis in chemotherapy-resistant tumor cell lines. IGF1R signaling regulates the expression of ABC transporter proteins via multiple mechanisms and renders chemotherapy less effective. The ECM interacts synergistically with IGF1R activity as chemotherapy-resistant cells develop; however, how this occurs remains unclear.

Overall, IGF1R signaling serves a crucial function in tumor chemotherapeutic tolerance. Recently, drug combinations that target predicted or identified chemoresistance markers have been suggested as the future direction of cancer treatment. As a membrane receptor, IGF1R is of particular interest in cancer drug targeting; however, IGF1R-mediated resistance mechanisms require further study. Furthermore, RTK heterodimer and IGF1R nuclear translocation may be associated with drug resistance, though few reports of this exist in the literature.

Acknowledgements

The present study was supported by the National Natural Science Foundation of China (grant no. 81572411).

References

1 

Cascieri MA and Bayne ML: Analysis of the interaction of IGF-I analogs with the IGF-I receptor and IGF binding proteins. Adv Exp Med Biol. 343:33–40. 1993. View Article : Google Scholar : PubMed/NCBI

2 

Hayashi Y, Asuzu DT, Gibbons SJ, Aarsvold KH, Bardsley MR, Lomberk GA, Mathison AJ, Kendrick ML, Shen KR, Taguchi T, et al: Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways. PLoS One. 8:e768222013. View Article : Google Scholar : PubMed/NCBI

3 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Amutha P and Rajkumar T: Role of insulin-like growth factor, insulin-like growth factor receptors, and insulin-like growth factor-binding proteins in ovarian cancer. Indian J Med Paediatr Oncol. 38:198–206. 2017.PubMed/NCBI

5 

Wan X, Harkavy B, Shen N, Grohar P and Helman LJ: Rapamycin induces feedback activation of akt signaling through an igf-1R-dependent mechanism. Oncogene. 26:1932–1940. 2007. View Article : Google Scholar : PubMed/NCBI

6 

Chen HX and Sharon E: IGF-1R as an anti-cancer target-trials and tribulations. Chin J Cancer. 32:242–252. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Shi WJ and Gao JB: Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol. 8:673–681. 2016. View Article : Google Scholar : PubMed/NCBI

8 

Liu JP, Baker J, Perkins AS, Robertson EJ and Efstratiadis A: Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 75:59–72. 1993. View Article : Google Scholar : PubMed/NCBI

9 

Ward CW and Garrett TP: Structural relationships between the insulin receptor and epidermal growth factor receptor families and other proteins. Curr Opin Drug Discov Devel. 7:630–638. 2004.PubMed/NCBI

10 

Siddle K: The insulin receptor and type I IGF receptor: Comparison of structure and function. Prog Growth Factor Res. 4:301–320. 1992. View Article : Google Scholar : PubMed/NCBI

11 

Wit JM and Walenkamp MJ: Role of insulin-like growth factors in growth, development and feeding. World Rev Nutr Diet. 106:60–65. 2013.PubMed/NCBI

12 

Yakar S, Kim H, Zhao H, Toyoshima Y, Pennisi P, Gavrilova O and Leroith D: The growth hormone-insulin like growth factor axis revisited: Lessons from IGF-1 and IGF-1 receptor gene targeting. Pediatr Nephrol. 20:251–254. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Russo VC, Gluckman PD, Feldman EL and Werther GA: The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev. 26:916–943. 2005. View Article : Google Scholar : PubMed/NCBI

14 

Laustsen PG, Russell SJ, Cui L, Entingh-Pearsall A, Holzenberger M, Liao R and Kahn CR: Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function. Mol Cell Biol. 27:1649–1664. 2007. View Article : Google Scholar : PubMed/NCBI

15 

Moody G, Beltran PJ, Mitchell P, Cajulis E, Chung YA, Hwang D, Kendall R, Radinsky R, Cohen P and Calzone FJ: IGF1R blockade with ganitumab results in systemic effects on the GH-IGF axis in mice. J Endocrinol. 221:145–155. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Delafontaine P, Song YH and Li Y: Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arterioscler Thromb Vasc Biol. 24:435–444. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Gao S, Wassler M, Zhang L, Li Y, Wang J, Zhang Y, Shelat H, Williams J and Geng YJ: MicroRNA-133a regulates insulin-like growth factor-1 receptor expression and vascular smooth muscle cell proliferation in murine atherosclerosis. Atherosclerosis. 232:171–179. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Werner H: Tumor suppressors govern insulin-like growth factor signaling pathways: Implications in metabolism and cancer. Oncogene. 31:2703–2714. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Schayek H, Bentov I, Sun S, Plymate SR and Werner H: Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene. Exp Cell Res. 316:1479–1488. 2010. View Article : Google Scholar : PubMed/NCBI

20 

O'Connor R, Kauffmann-Zeh A, Liu Y, Lehar S, Evan GI, Baserga R and Blättler WA: Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis. Mol Cell Biol. 17:427–435. 1997. View Article : Google Scholar : PubMed/NCBI

21 

Resnicoff M, Abraham D, Yutanawiboonchai W, Rotman HL, Kajstura J, Rubin R, Zoltick P and Baserga R: The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. Cancer Res. 55:2463–2469. 1995.PubMed/NCBI

22 

Valentinis B and Baserga R: The IGF-I receptor protects tumor cells from apoptosis induced by high concentrations of serum. Biochem Biophys Res Commun. 224:362–368. 1996. View Article : Google Scholar : PubMed/NCBI

23 

Baserga R: The IGF-I receptor in cancer research. Exp Cell Res. 253:1–6. 1999. View Article : Google Scholar : PubMed/NCBI

24 

Samani AA, Yakar S, LeRoith D and Brodt P: The role of the IGF system in cancer growth and metastasis: Overview and recent insights. Endocr Rev. 28:20–47. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Pollak M: The insulin and insulin-like growth factor receptor family in neoplasia: An update. Nat Rev Cancer. 12:159–169. 2012.PubMed/NCBI

26 

Ter Braak B, Siezen CL, Lee JS, Rao P, Voorhoeve C, Ruppin E, van der Laan JW and van de Water B: Insulin-like growth factor 1 receptor activation promotes mammary gland tumor development by increasing glycolysis and promoting biomass production. Breast Cancer Res. 19:142017. View Article : Google Scholar : PubMed/NCBI

27 

Peretz S, Kim C, Rockwell S, Baserga R and Glazer PM: IGF1 receptor expression protects against microenvironmental stress found in the solid tumor. Radiat Res. 158:174–180. 2002. View Article : Google Scholar : PubMed/NCBI

28 

Werner H, Sarfstein R, LeRoith D and Bruchim I: Insulin-like growth factor 1 signaling axis meets p53 genome protection pathways. Front Oncol. 6:1592016. View Article : Google Scholar : PubMed/NCBI

29 

Mamula PW and Goldfine ID: Cloning and characterization of the human insulin-like growth factor-I receptor gene 5′-flanking region. DNA Cell Biol. 11:43–50. 1992. View Article : Google Scholar : PubMed/NCBI

30 

Werner H, Bach MA, Stannard B, Roberts CT Jr and LeRoith D: Structural and functional analysis of the insulin-like growth factor I receptor gene promoter. Mol Endocrinol. 6:1545–1558. 1992. View Article : Google Scholar : PubMed/NCBI

31 

Singh RK, Gaikwad SM, Jinager A, Chaudhury S, Maheshwari A and Ray P: IGF-1R inhibition potentiates cytotoxic effects of chemotherapeutic agents in early stages of chemoresistant ovarian cancer cells. Cancer Lett. 354:254–262. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Schayek H, Bentov I, Rotem I, Pasmanik-Chor M, Ginsberg D, Plymate SR and Werner H: Transcription factor E2F1 is a potent transactivator of the insulin-like growth factor-I receptor (IGF-IR) gene. Growth Horm IGF Res. 20:68–72. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Huo X, Liu S, Shao T, Hua H, Kong Q, Wang J, Luo T and Jiang Y: GSK3 protein positively regulates type I insulin-like growth factor receptor through forkhead transcription factors FOXO1/3/4. J Biol Chem. 289:24759–72470. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Finkeltov I, Kuhn S, Glaser T, Idelman G, Wright JJ, Roberts CT Jr and Werner H: Transcriptional regulation of IGF-I receptor gene expression by novel isoforms of the EWS-WT1 fusion protein. Oncogene. 21:1890–1898. 2002. View Article : Google Scholar : PubMed/NCBI

35 

Werner H and Sarfstein R: Transcriptional and epigenetic control of IGF1R gene expression: Implications in metabolism and cance. Growth Horm IGF Res. 24:112–118. 2014. View Article : Google Scholar : PubMed/NCBI

36 

Idelman G, Glaser T, Roberts CT Jr and Werner H: WT1-p53 interactions in insulin-like growth factor-I receptor gene regulation. J Biol Chem. 278:3474–3482. 2003. View Article : Google Scholar : PubMed/NCBI

37 

Kim SO, Park JG and Lee YI: Increased expression of the insulin-like growth factor I (IGF-I) receptor gene in hepatocellular carcinoma cell lines: Implications of IGF-I receptor gene activation by hepatitis B virus X gene product. Cancer Res. 56:3831–3836. 1996.PubMed/NCBI

38 

Taliaferro-Smith L, Oberlick E, Liu T, McGlothen T, Alcaide T, Tobin R, Donnelly S, Commander R, Kline E, Nagaraju GP, et al: FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells. Oncotarget. 6:4757–4772. 2015. View Article : Google Scholar : PubMed/NCBI

39 

Dearth RK, Cui X, Kim HJ, Hadsell DL and Lee AV: Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. Cell Cycle. 6:705–713. 2007. View Article : Google Scholar : PubMed/NCBI

40 

Koval AP, Blakesley VA, Roberts CT Jr, Zick Y and Leroith D: Interaction in vitro of the product of the c-Crk-II proto-oncogene with the insulin-like growth factor I receptor. Biochem J. 330:923–932. 1998. View Article : Google Scholar : PubMed/NCBI

41 

Kulik G and Weber MJ: Akt-dependent and -independent survival signaling pathways utilized by insulin-like growth factor I. Mol Cell Biol. 18:6711–6718. 1998. View Article : Google Scholar : PubMed/NCBI

42 

Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B and Baserga R: Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol Cell Biol. 19:7203–7215. 1999. View Article : Google Scholar : PubMed/NCBI

43 

Brazil DP, Yang ZZ and Hemmings BA: Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci. 29:233–242. 2004. View Article : Google Scholar : PubMed/NCBI

44 

Pollak M: Insulin, insulin-like growth factors and neoplasia. Best Pract Res Clin Endocrinol Metab. 22:625–638. 2008. View Article : Google Scholar : PubMed/NCBI

45 

Greer EL and Brunet A: FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 24:7410–7425. 2005. View Article : Google Scholar : PubMed/NCBI

46 

Playford MP, Bicknell D, Bodmer WF and Macaulay VM: Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Proc Natl Acad Sci USA. 97:pp. 12103–12108. 2000; View Article : Google Scholar : PubMed/NCBI

47 

Liu C, Zhang Z, Tang H, Jiang Z, You L and Liao Y: Crosstalk between IGF-1R and other tumor promoting pathways. Curr Pharm Des. 20:2912–2921. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Rota LM, Albanito L, Shin ME, Goyeneche CL, Shushanov S, Gallagher EJ, LeRoith D, Lazzarino DA and Wood TL: IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors. Cancer Res. 74:5668–5679. 2014. View Article : Google Scholar : PubMed/NCBI

49 

Zhang QY, Wang L, Song ZY and Qu XJ: Knockdown of type I insulin-like growth factor receptor inhibits human colorectal cancer cell growth and downstream PI3K/Akt, WNT/β-catenin signal pathways. Biomed Pharmacother. 73:12–18. 2015. View Article : Google Scholar : PubMed/NCBI

50 

Alsina-Sanchis E, Figueras A, Lahiguera Á, Vidal A, Casanovas O, Graupera M, Villanueva A and Vinals F: The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels. Int J Cancer. 139:1894–4903. 2016. View Article : Google Scholar : PubMed/NCBI

51 

Tognon CE and Sorensen PH: Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy. Expert Opin Ther Targets. 16:33–48. 2012. View Article : Google Scholar : PubMed/NCBI

52 

Firth SM and Baxter RC: Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 23:824–854. 2002. View Article : Google Scholar : PubMed/NCBI

53 

Triplett TA, Cardenas KT, Lancaster JN, Hu Z, Selden HJ, Jasso GJ, Balasubramanyam S, Chan K, Li L, Chen X, et al: Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation. Proc Natl Acad Sci USA. 113:pp. E1016–E1025. 2016; View Article : Google Scholar : PubMed/NCBI

54 

Medyouf H, Gusscott S, Wang H, Tseng JC, Wai C, Nemirovsky O, Trumpp A, Pflumio F, Carboni J, Gottardis M, et al: High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling. J Exp Med. 208:1809–1822. 2011. View Article : Google Scholar : PubMed/NCBI

55 

Manning BD and Cantley LC: AKT/PKB signaling: Navigating downstream. Cell. 129:1261–1274. 2007. View Article : Google Scholar : PubMed/NCBI

56 

Kim EK, Kim JH, Kim HA, Seol H, Seong MK, Lee JY, Byeon J, Sohn YJ, Koh JS, Park IC and Noh WC: Phosphorylated S6 kinase-1: A breast cancer marker predicting resistance to neoadjuvant chemotherapy. Anticancer Res. 33:4073–4079. 2013.PubMed/NCBI

57 

Sui P, Cao H, Meng L, Hu P, Ma H and Du J: The synergistic effect of humanized monoclonal antibodies targeting insulin-like growth factor 1 receptor (IGF-1R) and chemotherapy. Curr Drug Targets. 15:674–680. 2014. View Article : Google Scholar : PubMed/NCBI

58 

Ge J and Chen Z, Wu S, Chen J, Li X, Li J, Yin J and Chen Z: Expression levels of insulin-like growth factor-1 and multidrug resistance-associated protein-1 indicate poor prognosis in patients with gastric cancer. Digestion. 80:148–158. 2009. View Article : Google Scholar : PubMed/NCBI

59 

de Groot S, Charehbili A, van Laarhoven HW, Mooyaart AL, Dekker-Ensink NG, van de Ven S, Janssen LG, Swen JJ, Smit VT, Heijns JB, et al: Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: Results from the NEOZOTAC trial (BOOG 2010-01). Breast Cancer Res. 18:32016. View Article : Google Scholar : PubMed/NCBI

60 

Sun HZ, Wu SF and Tu ZH: Blockage of IGF-1R signaling sensitizes urinary bladder cancer cells to mitomycin-mediated cytotoxicity. Cell Res. 11:107–115. 2001. View Article : Google Scholar : PubMed/NCBI

61 

Thomas F, Holly JM, Persad R, Bahl A and Perks CM: Fibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: involvement of the insulin like growth factor-1 receptor. Prostate. 70:856–865. 2010.PubMed/NCBI

62 

Eckstein N, Servan K, Hildebrandt B, Pölitz A, von Jonquières G, Wolf-Kümmeth S, Napierski I, Hamacher A, Kassack MU, Budczies J, et al: Hyperactivation of the insulin-like growth factor receptor I signaling pathway is an essential event for cisplatin resistance of ovarian cancer cells. Cancer Res. 69:2996–3003. 2009. View Article : Google Scholar : PubMed/NCBI

63 

Montazami N, Aghapour M, Farajnia S and Baradaran B: New insights into the mechanisms of multidrug resistance in cancers. Cell Mol Biol (Noisy-le-grand). 61:70–80. 2015.PubMed/NCBI

64 

Worrall C, Nedelcu D, Serly J, Suleymanova N, Oprea I, Girnita A and Girnita L: Novel mechanisms of regulation of IGF-1R action: Functional and therapeutic implications. Pediatr Endocrinol Rev. 10:473–484. 2013.PubMed/NCBI

65 

Chen MY, Clark AJ, Chan DC, Ware JL, Holt SE, Chidambaram A, Fillmore HL and Broaddus WC: Wilms' tumor 1 silencing decreases the viability and chemoresistance of glioblastoma cells in vitro: A potential role for IGF-1R de-repression. J Neurooncol. 103:87–102. 2011. View Article : Google Scholar : PubMed/NCBI

66 

Qian X, Yu J, Yin Y, He J, Wang L, Li Q, Zhang LQ, Li CY, Shi ZM, Xu Q, et al: MicroRNA-143 inhibits tumor growth and angiogenesis and sensitizes chemosensitivity to oxaliplatin in colorectal cancers. Cell Cycle. 12:1385–1394. 2013. View Article : Google Scholar : PubMed/NCBI

67 

Wang T, Ge G, Ding Y, Zhou X, Huang Z, Zhu W, Shu Y and Liu P: MiR-503 regulates cisplatin resistance of human gastric cancer cell lines by targeting IGF1R and BCL2. Chin Med J (Engl). 127:2357–2362. 2014.PubMed/NCBI

68 

Yang M, Shan X, Zhou X, Qiu T, Zhu W, Ding Y, Shu Y and Liu P: miR-1271 regulates cisplatin resistance of human gastric cancer cell lines by targeting IGF1R, IRS1, mTOR, and BCL2. Anticancer Agents Med Chem. 14:884–891. 2014. View Article : Google Scholar : PubMed/NCBI

69 

Zhuang M, Shi Q, Zhang X, Ding Y, Shan L, Shan X, Qian J, Zhou X, Huang Z, Zhu W, et al: Involvement of miR-143 in cisplatin resistance of gastric cancer cells via targeting IGF1R and BCL2. Tumour Biol. 36:2737–2745. 2015. View Article : Google Scholar : PubMed/NCBI

70 

Verhagen HJ, de Leeuw DC, Roemer MG, Denkers F, Pouwels W, Rutten A, Celie PH, Ossenkoppele GJ, Schuurhuis GJ and Smit L: IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival. Cell Death Dis. 5:e13002014. View Article : Google Scholar : PubMed/NCBI

71 

Baxter RC: Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab. 278:E967–E976. 2000.PubMed/NCBI

72 

Bach LA: Insulin-like growth factor binding proteins-an update. Pediatr Endocrinol Rev. 13:521–530. 2015.PubMed/NCBI

73 

Beattie J, Allan GJ, Lochrie JD and Flint DJ: Insulin-like growth factor-binding protein-5 (IGFBP-5): A critical member of the IGF axis. Biochem J. 395:1–19. 2006. View Article : Google Scholar : PubMed/NCBI

74 

Beech DJ, Perer E, Helms J, Gratzer A and Deng N: Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells. Oncol Rep. 10:181–184. 2003.PubMed/NCBI

75 

Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G II, Samuel S, Kim MP, Lim SJ and Ellis LM: Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 69:1951–1957. 2009. View Article : Google Scholar : PubMed/NCBI

76 

Sun Y, Zheng S, Torossian A, Speirs CK, Schleicher S, Giacalone NJ, Carbone DP, Zhao Z and Lu B: Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells. Int J Radiat Oncol Biol Phys. 82:e563–e572. 2012. View Article : Google Scholar : PubMed/NCBI

77 

Kim TR, Cho EW, Paik SG and Kim IG: Hypoxia-induced SM22α in A549 cells activates the IGF1R/PI3K/Akt pathway, conferring cellular resistance against chemo- and radiation therapy. FEBS Lett. 586:303–309. 2012. View Article : Google Scholar : PubMed/NCBI

78 

Werner H and Le Roith D: New concepts in regulation and function of the insulin-like growth factors: Implications for understanding normal growth and neoplasia. Cell Mol Life Sci. 57:932–942. 2000. View Article : Google Scholar : PubMed/NCBI

79 

Tracz AF, Szczylik C, Porta C and Czarnecka AM: Insulin-like growth factor-1 signaling in renal cell carcinoma. BMC Cancer. 16:4532016. View Article : Google Scholar : PubMed/NCBI

80 

Buck E and Mulvihill M: Small molecule inhibitors of the IGF-1R/IR axis for the treatment of cancer. Expert Opin Investig Drugs. 20:605–621. 2011. View Article : Google Scholar : PubMed/NCBI

81 

Ozaki T and Nakagawara A: P53: The attractive tumor suppressor in the cancer research field. J Biomed Biotechnol. 2011:6039252011. View Article : Google Scholar : PubMed/NCBI

82 

Larsson O, Girnita A and Girnita L: Role of insulin-like growth factor 1 receptor signalling in cancer. Br J Cancer. 96 Suppl:R2–R6. 2007.PubMed/NCBI

83 

Adams JM and Cory S: Bcl-2-regulated apoptosis: Mechanism and therapeutic potential. Curr Opin Immunol. 19:488–496. 2007. View Article : Google Scholar : PubMed/NCBI

84 

Kashyap MK: Role of insulin-like growth factor-binding proteins in the pathophysiology and tumorigenesis of gastroesophageal cancers. Tumour Biol. 36:8247–8257. 2015. View Article : Google Scholar : PubMed/NCBI

85 

Jiang ZS, Sun YZ, Wang SM and Ruan JS: Epithelial-mesenchymal transition: Potential regulator of ABC transporters in tumor progression. J Cancer. 8:2319–2327. 2017. View Article : Google Scholar : PubMed/NCBI

86 

Zhang YK, Wang YJ, Gupta P and Chen ZS: Multidrug resistance proteins (MRPs) and cancer therapy. AAPS J. 17:802–812. 2015. View Article : Google Scholar : PubMed/NCBI

87 

Benabbou N, Mirshahi P, Bordu C, Faussat AM, Tang R, Therwath A, Soria J, Marie JP and Mirshahi M: A subset of bone marrow stromal cells regulate ATP-binding cassette gene expression via insulin-like growth factor-I in a leukemia cell line. Int J Oncol. 45:1372–1380. 2014. View Article : Google Scholar : PubMed/NCBI

88 

Shen K, Cui D, Sun L, Lu Y, Han M and Liu J: Inhibition of IGF-IR increases chemosensitivity in human colorectal cancer cells through MRP-2 promoter suppression. J Cell Biochem. 113:2086–2097. 2012. View Article : Google Scholar : PubMed/NCBI

89 

Benabbou N, Mirshahi P, Cadillon M, Soria J, Therwath A and Mirshahi M: Hospicells promote upregulation of the ATP-binding cassette genes by insulin-like growth factor-I via the JAK2/STAT3 signaling pathway in an ovarian cancer cell line. Int J Oncol. 43:685–694. 2013. View Article : Google Scholar : PubMed/NCBI

90 

Gilkes DM, Semenza GL and Wirtz D: Hypoxia and the extracellular matrix: Drivers of tumour metastasis. Nat Rev Cancer. 14:430–439. 2014. View Article : Google Scholar : PubMed/NCBI

91 

Elliott T and Sethi T: Integrins and extracellular matrix: A novel mechanism of multidrug resistance. Expert Rev Anticancer Ther. 2:449–459. 2002. View Article : Google Scholar : PubMed/NCBI

92 

L Addison C: Modulation of response to tumor therapies by the extracellular matrix. Future Oncol. 2:417–429. 2006. View Article : Google Scholar : PubMed/NCBI

93 

Sayeed A, Fedele C, Trerotola M, Ganguly KK and Languino LR: IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels. PLoS One. 8:e765132013. View Article : Google Scholar : PubMed/NCBI

94 

Prokop I, Konończuk J, Surażyński A and Pałka J: Cross-talk between integrin receptor and insulin-like growth factor receptor in regulation of collagen biosynthesis in cultured fibroblasts. Adv Med Sci. 58:292–297. 2013. View Article : Google Scholar : PubMed/NCBI

95 

Packham S, Warsito D, Lin Y, Sadi S, Karlsson R, Sehat B and Larsson O: Nuclear translocation of IGF-1R via p150(Glued) and an importin-β/RanBP2-dependent pathway in cancer cells. Oncogene. 34:2227–2238. 2015. View Article : Google Scholar : PubMed/NCBI

96 

Aleksic T, Chitnis MM, Perestenko OV, Gao S, Thomas PH, Turner GD, Protheroe AS, Howarth M and Macaulay VM: Type 1 insulin-like growth factor receptor translocates to the nucleus of human tumor cells. Cancer Res. 70:6412–6419. 2010. View Article : Google Scholar : PubMed/NCBI

97 

Sehat B, Tofigh A, Lin Y, Trocmé E, Liljedahl U, Lagergren J and Larsson O: SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor. Sci Signal. 3:ra102010. View Article : Google Scholar : PubMed/NCBI

98 

Sarfstein R, Pasmanik-Chor M, Yeheskel A, Edry L, Shomron N, Warman N, Wertheimer E, Maor S, Shochat L and Werner H: Insulin-like growth factor-I receptor (IGF-IR) translocates to nucleus and autoregulates IGF-IR gene expression in breast cancer cells. J Biol Chem. 287:2766–2776. 2012. View Article : Google Scholar : PubMed/NCBI

99 

Vesel M, Rapp J, Feller D, Kiss E, Jaromi L, Meggyes M, Miskei G, Duga B, Smuk G, Laszlo T, et al: ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling. Respir Res. 18:522017. View Article : Google Scholar : PubMed/NCBI

100 

Huang YH, Lin MH, Wang PC, Wu YC, Chiang HL, Wang YL, Chang JH, Huang YK, Gu SY, Ho HN and Ling TY: Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells. Mol Hum Reprod. 20:526–537. 2014. View Article : Google Scholar : PubMed/NCBI

101 

Treins C, Giorgetti-Peraldi S, Murdaca J, Monthouël-Kartmann MN and Van Obberghen E: Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I. Mol Endocrinol. 19:1304–1317. 2005. View Article : Google Scholar : PubMed/NCBI

102 

Popeda M, Pluciennik E and Bednarek AK: Proteins in cancer multidrug resistance. Postepy Hig Med Dosw (Online). 68:616–632. 2014.(In Polish). View Article : Google Scholar : PubMed/NCBI

103 

Genois MM, Paquet ER, Laffitte MC, Maity R, Rodrigue A, Ouellette M and Masson JY: DNA repair pathways in trypanosomatids: From DNA repair to drug resistance. Microbiol MoI Biol Rev. 78:40–73. 2014. View Article : Google Scholar

Related Articles

Journal Cover

January-2018
Volume 15 Issue 1

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Yuan J, Yin Z, Tao K, Wang G and Gao J: Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review). Oncol Lett 15: 41-47, 2018
APA
Yuan, J., Yin, Z., Tao, K., Wang, G., & Gao, J. (2018). Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review). Oncology Letters, 15, 41-47. https://doi.org/10.3892/ol.2017.7276
MLA
Yuan, J., Yin, Z., Tao, K., Wang, G., Gao, J."Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)". Oncology Letters 15.1 (2018): 41-47.
Chicago
Yuan, J., Yin, Z., Tao, K., Wang, G., Gao, J."Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)". Oncology Letters 15, no. 1 (2018): 41-47. https://doi.org/10.3892/ol.2017.7276