The importance of Src signaling in sarcoma (Review)

  • Authors:
    • Quanchi Chen
    • Zifei Zhou
    • Liancheng Shan
    • Hui Zeng
    • Yingqi Hua
    • Zhengdong Cai
  • View Affiliations

  • Published online on: May 6, 2015     https://doi.org/10.3892/ol.2015.3184
  • Pages: 17-22
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.

Introduction

Sarcoma is a soft-tissue and bone malignancy of mesenchymal origin, which accounts for ~1% of adult cancers and 15–20% of pediatric cancers in the USA (1,2). In the USA, ~11,280 soft tissue tumors and 2,650 bone tumors are diagnosed annually (3). Due to the heterogeneity of sarcoma, >100 distinct subtypes have been described to date, with new subtypes frequently reported (4). Synovial sarcoma, a soft-tissue tumor, is characterized by a reciprocal t(X;18) translocation, in which the SS18 gene on chromosome 18 fuses with the SSX1, SSX2 or, less commonly, SSX4 gene on the X chromosome (5,6). Ewing's sarcoma has a relatively simple genetic signature, consisting of a t(11;22) translocation (7,8). However, certain other sarcomas, including osteosarcoma, chondrosarcoma and undifferentiated sarcoma, are characterized by more complex genetic abnormalities (9).

The clinical outcomes of sarcoma are dependent upon the subtype, and current therapies are limited to radiation, chemotherapy and surgical resection. Although radiation may prevent local recurrence, and chemotherapy can temporarily delay the progression of sarcoma, complete surgical resection is the only curative treatment method (10,11). As the rate of complication and of chemotherapy resistance are considerable, a more effective therapy is urgently required (12). During the last two decades, many of the molecular mechanisms of sarcoma genesis have been elucidated; novel insights into such mechanisms, and the identification of the involved genes may lead to the development of more effective therapies targeted against the driving events in sarcomas (13).

In the current review, the structure of Src and its function as an oncoprotein are described, with a detailed discussion of the role of Src in sarcoma. In addition, potential drug therapies for the treatment of sarcoma are also evaluated.

Src

Src structure and regulation of Src activity

SRC is a proto-oncogene encoding a non-receptor tyrosine kinase, similar to the v-Src gene of the Rous sarcoma virus (14), which was initially discovered by Bishop and Varmus (15). The Src protein is formed of seven functional regions: i) N-terminal Src homology domain 4 (SH4) containing a myristic acid moiety, essential for its localization to the inner surface of the cell membrane; ii) a unique domain providing functional specificity to each member of the Src family; iii) SH3 domain, which binds proline-rich sequences to mediate intra- and intermolecular interactions; iv) SH2 domain, which binds phosphorylated tyrosine residues on Src and other proteins; v) a catalytic domain (SH1); and vi) C-terminal tail containing negative-regulatory Tyr530 (in humans) (1618) (Fig. 1).

The activity of Src is regulated by the structural changes that occur following phosphorylation and dephosphorylation of its tyrosine residues, which is determined by the relative activities of protein kinases and phosphatases (19). The enzymatic activity of the 60 kDa human c-Src tyrosine kinase is predominantly regulated at two phosphorylation sites: Tyr527 and Tyr416. Phosphorylation at Tyr527 reduces the activity of Src, while dephosphorylation of phosphotyrosine 527 increases activity; autophosphorylation of Tyr416 also enhances activity (20,21). Phosphatases that may interact with phosphotyrosine 527 include cytoplasmic protein tyrosine phosphatase (PTP) 1B, Shp1 and Shp2, and transmembrane enzymes including CD45, PTPα, PTPε, and PTPκ (22,23). Furthermore, PTP-BL and PTP-BAS have been shown to dephosphorylate phosphotyrosine 416 to decrease Src kinase activity (24) (Fig. 2).

Functions of Src in cancer

Src has been identified as an important factor in several human malignancies, and in the promotion of tumor progression during the multistep process of cancer pathogenesis (25). Src deregulation primarily involves protein overexpression and abnormalities in Src kinase activity. Differences in Src expression have been observed in lung, breast, pancreatic, colon and prostate cancer cells, compared with normal adjacent tissue, fibroblasts or normal mucosal cells (2631). In the tumor microenvironment, Src activation has been observed in cancer and inflammatory cells, and may serve as a critical mechanistic link between inflammation and cancer. Src propagates a cycle between immune and tissue cells, ultimately leading to the development and progression of cancer (32,33). The abnormal activation of Src may result in the promotion of survival, angiogenesis, proliferation and invasion pathways observed in tumors cells (34,35). However, despite the evidence indicating a major role for Src in the development and progression of cancers, its mechanism of action is not fully understood.

A number experimental studies have proposed that Src may be involved in the transmission of signals from extra and intracellular stimuli. Interactions between the Src pathway and Signal Transducer and Activator of Transcription (STAT) 5, STAT3, N-cadherin and basic fibroblast growth factor receptors and β-catenin have been reported in melanoma cells (36,37). It may also be of value to understand the effect of Src inhibition on a number of the environment-sensing and growth-promoting pathways known to be aberrant in cancer cells, including the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), Ras/mitogen-activated protein kinase (MAPK), platelet-derived growth factor (PDGF), Erb1/Erb2 and vascular endothelial growth factor (VEGF) pathways (3840). Currently, the complex interactions between Src and other pathways remain to be established. The crosstalk signaling mechanisms that link inflammatory cells with cancer cells, including SDF-1-CXCR4-Src and Src-IL-6 signaling axes, result in a cycle leading to cancer development and progression (4143). In leukemia, SDF-1 has been found to induce ‘inside-out’ signaling, which involves CXCR4 and Lyn, leading to aberrant adhesive responses. Furthermore, previous studies have shown that Src and Hck, the Src family members, are involved in the production of IL-6 in osteoblasts and inflammatory macrophages (42,43).

Function of Src in sarcoma

Src aberrant expression in sarcoma

Src was the first transforming protein and the first gene product with protein tyrosine kinase activity to be discovered and isolated (44). With the use of immunohistochemistry and Western blotting, the total Src and phosphorylated Src (Y419) were found to be activated in human sarcoma tissues (leiomyosarcoma, high-grade osteosarcoma and liposarcoma) and sarcoma cell lines (osteosarcoma, Ewing's sarcoma, leiomyosarcoma and rhabdomyosarcoma) (45). Furthermore, Src was identified as one of the most strongly phosphorylated kinases in synovial sarcoma cells (46). Src activity was demonstrated to be upregulated in anoikis-resistant human osteosarcoma cells, SAOS-2, compared with their parental population (47).

With regard to different subtypes of sarcoma, Src is thought to be the most reliable discriminator to distinguish high-grade leiomyosarcoma from undifferentiated pleomorphic sarcoma, based on gene expression profiling and meta-analysis (48). Due to its aberrant expression in sarcoma, Src has been proposed to be important in signal transduction in human sarcomas, including osteosarcoma, rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma and Ewing's sarcoma (49).

Src in sarcoma proliferation and apoptosis

A fundamental trait of cancer cells is their ability to sustain chronic proliferation. The overexpression of Src in U2OS and MG63 osteosarcoma cells significantly enhances proliferation and reduces apoptosis of these cells (45,50). In human osteosarcoma cells SAOS-2, Src was revealed to be activated in anoikis resistance (47). Furthermore, Src was identified in 0–20% chondrosarcoma specimens. However, its expression had no prognostic significance, particularly in serving as an indicator of cell proliferation (51). Src and its downstream signaling via the p38 MAPK-AKT pathway may be activated by the signaling adaptor protein, Crk, to promote proliferation of human synovial sarcoma cells (52,53). Inhibition of Src signaling in Ewing's sarcoma cells was observed to induce apoptosis (45).

These findings indicate that Src may increase sarcoma proliferation and reduce apoptosis. However, in some subtypes of sarcoma, there is conflicting evidence with regard to the expression of Src. For example, high Src expression has been identified in high-grade leiomyosarcoma, while Src expression has been found to be variable in chondrosarcoma (48). Additionally, the mechanisms of proliferation and apoptosis require further investigation.

Src in sarcoma invasion and metastasis

Despite continual research and increasing knowledge of the biology of sarcoma, invasion and metastasis remain poorly understood, and are the predominant cause of sarcoma-related mortality. The ability of cancer cells to leave their primary site of growth, move into different tissue compartments, and survive and proliferate in these foreign environments, defines the biological program known as ‘invasive growth’ (54). Invasive growth is important for cancer progression and thus, presents a target for the treatment of sarcoma. In mouse models of osteosarcoma, depletion of Src phosphorylation in SaOS-2 cells has been shown to decrease tumor mass (55). However, other reports indicate that inhibition of Src phosphorylation in HOS and SaOS-2 cells may only decrease the metastatic potential of osteosarcoma cells in vitro, and not in vivo (56). The effect of Src on the metastasis of osteosarcoma cells is therefore controversial. A number of studies reported that inhibition of c-Src signaling was able to reduce metastasis of chondrosarcoma (57,58). Other studies found that Src inhibition could overcome chemoresistance to induce apoptosis and to inhibit migration (59). In Ewing's sarcoma cells, inhibition of c-Src was also observed to reduce migration and metastasis (45).

It has been established that epithelial cells may acquire migratory capability, a feature typical of the mesenchymal cells, and gain invasive ability, resistance to apoptosis and the ability to disseminate (60), in a process known as the epithelial-mesenchymal transition (EMT). EMT is a complicated process, whereby cancer cells acquire migratory and invasive abilities, which are influenced by the tumor microenvironment and intercellular communication. Src activity affects metastatic progression, suggesting that Src-induced EMT may be associated with enhanced metastatic potential (61). However, the effect of Src-related EMT has yet to be investigated in sarcoma.

Src signaling networks in sarcoma

A number of studies have provided insight into how Src overexpression and activation may contribute to cancer. CD99, a transmembrane glycoprotein, may exert anti-oncogenic effects, reducing the growth and metastatic ability of osteosarcoma cells by regulating Caveolin-1 (Cav-1) and inhibiting Src kinase activity. Cav-1 is a caveolar domain associated with the plasma membrane, which is involved in numerous cellular functions, including molecular transport, cell adhesion and signal transduction and thus, the role of Cav-1 in cancer development and progression has been investigated (62,63). Cav-1 may act as an onco-suppressor and inhibit Src to reduce osteosarcoma metastasis (64,65). However, other studies have demonstrated that CD99 isoforms, CD99wt (full-length CD99 isoform) and CD99sh (short form) have opposing effects in osteosarcoma malignancy and metastasis, and may activate or inhibit Src kinase activity (66).

In osteosarcoma, when Src was inhibited, the downstream components of Src signaling, including focal adhesion kinase (FAK) and a partnership and Crk-associated substrate (p130CAS) were also inhibited at the protein level. In rhabdomyosarcoma, targeting the Src-α-type platelet-derived growth factor receptor-Raf-MAPK axis has been shown to be effective in inhibiting mouse and human tumor cell growth (67).

Clinical development of Src inhibitors

Src has recently become an active target for drug development and a number of Src inhibitors, including dasatinib (BMS354825), sarcatinib (AZD0530) and bosutinib (SKI-606), are at various stages in the development process (68). Dasatinib has been approved for the treatment of chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia (69), saracatinib has been used in a phase II trial for the treatment of extensive stage small cell lung cancer (70), and bosutinib has been used in a phase II trial for the treatment of adults with recurrent glioblastoma (71).

Dasatinib is a dual Src-AbI kinase inhibitor, which is already approved by the Food and Drug Administration for the treatment of chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia (72). Several studies have demonstrated the therapeutic benefit of dasatinib in preventing the growth and metastasis of sarcomas. In osteosarcoma cell lines, wound-healing, cell migration and TUNEL assays indicated that dasatinib may block cell motility and invasion, and induce apoptosis (45,73). In chondrosarcoma, dasatinib was also capable of decreasing tumor growth, however, it was unable to reduce invasion (73).

A new pyrazolo[3,4-d] pyrimidine derivative Src-Y416 inhibitor (SI-83) was found to impair osteosarcoma SaOS-2 cell viability and decrease osteosarcoma tumor mass in vivo, and exhibited less toxicity in primary human osteoblasts when compared with osteosarcoma cells. Additionally, SI-83 was shown to induce apoptosis in SaOS-2 cells (55). These results indicate that SI-83 may be a novel effective therapeutic agent, with the advantage of low toxicity in nonneoplastic cells. A number of tyrosine kinase inhibitors that target Src tyrosine kinase have also been developed for therapeutic use (74), such as the pan-RAF inhibitors, CCT196969 and CCT241161 (75).

Conclusion

Compared with normal tissue, Src expression is significantly higher in tumor tissue, including gastrointestinal stromal tumors and renal clear cell carcinomas (76,77). A number of studies have found that Src signaling is important in attracting immune cells to tumor cells (32). The activation of Src, mediated by inflammatory cytokines and chemokines within the tumor microenvironment, occurs in cancer cells and immune inflammatory cells (78,79).

However, due to the intra- and inter-tumor heterogeneity, targeting a single genetic event in sarcoma is unlikely to produce favorable clinical outcomes. Furthermore, understanding the role of Src in the initiation and progression of sarcoma is at an early stage, and the mechanisms by which Src affects the sarcoma microenvironment and the immune system remain to be investigated. Optimal treatment may include surgical resection combined with therapies that target the functional processes involved in tumor biology and metastasis, including chemotherapy and immunomodulation (80,81). The Src protein exhibits high specificity and a positive predictive value, highlighting its potential as a diagnostic marker for certain types of sarcoma, such as osetosarcoma and Ewing's sarcoma. Thus, Src inhibitors may present a novel type of chemotherapeutic drug for the treatment of sarcoma, however, preclinical studies to determine the optimal protein sequence for Src-targeted treatments and methods to monitor the theapeutic effects of such are required.

Acknowledgments

This work was supported by National Natural Science Foundation of China (grant no. 81202115), the Key Project of Basic Research of Shanghai (grant no. 11JC1410101), the Shanghai Pujiang Program (grant no. 12PJ1407100), and the Excellent Young Talent Program (grant no. XYQ2013108).

References

1 

Valkov A, Kilvaer TK, Sorbye SW, et al: The prognostic impact of Akt isoforms, PI3K and PTEN related to female steroid hormone receptors in soft tissue sarcomas. J Transl Med. 9:2002011. View Article : Google Scholar : PubMed/NCBI

2 

Helman LJ and Meltzer P: Mechanisms of sarcoma development. Nat Rev Cancer. 3:685–694. 2003. View Article : Google Scholar : PubMed/NCBI

3 

Coindre JM: New WHO classification of tumours of soft tissue and bone. Ann Pathol. 32:S115–S116. 2012.(In French). PubMed/NCBI

4 

Klein MJ and Siegal GP: Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol. 125:555–581. 2006. View Article : Google Scholar : PubMed/NCBI

5 

de Bruijn DR, Allander SV, van Dijk AH, et al: The synovial-sarcoma-associated SS18-SSX2 fusion protein induces epigenetic gene (de)regulation. Cancer Res. 66:9474–9482. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Sun Y, Gao D, Liu Y, Huang J, Lessnick S and Tanaka S: IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1. Oncogene. 25:1042–1052. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Kashima TG, Gamage NG, Dirksen U, Gibbons CL, Ostlere SJ and Athanasou NA: Localized Ewing sarcoma of the tibia. Clin Sarcoma Res. 3:22013. View Article : Google Scholar : PubMed/NCBI

8 

Choi EY, Gardner JM, Lucas DR, McHugh JB and Patel RM: Ewing sarcoma. Semin Diagn Pathol. 31:39–47. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Kämmerer PW, Shabazfar N, Vorkhshori Makoie N, Moergel M and Al-Nawas B: Clinical, therapeutic and prognostic features of osteosarcoma of the jaws - experience of 36 cases. J Craniomaxillofac Surg. 40:541–548. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Steen S and Stephenson G: Current treatment of soft tissue sarcoma. In: Proc (Bayl Univ Med Cent). 21. pp. 392–396. 2008; PubMed/NCBI

11 

von Mehren M, Randall RL, Benjamin RS, et al: National Comprehensive Cancer Network: Soft tissue sarcoma, version 2.2014. J Natl Compr Canc Netw. 12:473–483. 2014.PubMed/NCBI

12 

Clark MA, Fisher C, Judson I and Thomas JM: Soft-tissue sarcomas in adults. N Engl J Med. 353:701–711. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Demicco EG, Maki RG, Lev DC and Lazar AJ: New therapeutic targets in soft tissue sarcoma. Adv Anat Pathol. 19:170–180. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Byeon SE, Yi YS, Oh J, Yoo BC, Hong S and Cho JY: The role of Src kinase in macrophage-mediated inflammatory responses. Mediators Inflamm. 2012:5129262012.PubMed/NCBI

15 

Levinson WE, Varmus HE, Garapin AC and Bishop JM: DNA of Rous sarcoma virus: its nature and significance. Science. 175:76–78. 1972. View Article : Google Scholar : PubMed/NCBI

16 

Gojis O, Rudraraju B, Gudi M, et al: The role of SRC-3 in human breast cancer. Nat Rev Clin Oncol. 7:83–89. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Boggon TJ and Eck MJ: Structure and regulation of Src family kinases. Oncogene. 23:7918–7927. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Guarino M: Src signaling in cancer invasion. J Cell Physiol. 223:14–26. 2010.PubMed/NCBI

19 

Hunter T and Sefton BM: Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. In: Proc Natl Acad Sci USA. 77. pp. 1311–1315. 1980; View Article : Google Scholar : PubMed/NCBI

20 

Roskoski R Jr: Src kinase regulation by phosphorylation and dephosphorylation. Biochem Biophys Res Commun. 331:1–14. 2005. View Article : Google Scholar : PubMed/NCBI

21 

Bjorge JD, Jakymiw A and Fujita DJ: Selected glimpses into the activation and function of Src kinase. Oncogene. 19:5620–5635. 2000. View Article : Google Scholar : PubMed/NCBI

22 

Zheng XM, Resnick RJ and Shalloway D: A phosphotyrosine displacement mechanism for activation of Src by PTPalpha. EMBO J. 19:964–978. 2000. View Article : Google Scholar : PubMed/NCBI

23 

Cooper JA, Gould KL, Cartwright CA and Hunter T: Tyr527 is phosphorylated in pp60c-src: implications for regulation. Science. 231:1431–1434. 1986. View Article : Google Scholar : PubMed/NCBI

24 

Levin VA: Basis and importance of Src as a target in cancer. Cancer Treat Res. 119:89–119. 2004.PubMed/NCBI

25 

Sirvent A, Benistant C and Roche S: Oncogenic signaling by tyrosine kinases of the SRC family in advanced colorectal cancer. Am J Cancer Res. 2:357–371. 2012.PubMed/NCBI

26 

Cao M, Hou D, Liang H, et al: miR-150 promotes the proliferation and migration of lung cancer cells by targeting SRC kinase signalling inhibitor 1. Eur J Cancer. 50:1013–1024. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Roskoski R Jr: Src protein-tyrosine kinase structure and regulation. Biochem Biophys Res Commun. 324:1155–1164. 2004. View Article : Google Scholar : PubMed/NCBI

28 

Zhang S, Huang WC, Zhang L, et al: SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases. Cancer Res. 73:5764–5774. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Gargalionis AN, Karamouzis MV and Papavassiliou AG: The molecular rationale of Src inhibition in colorectal carcinomas. Int J Cancer. 134:2019–2029. 2014. View Article : Google Scholar : PubMed/NCBI

30 

Je DW, O YM, Ji YG, Cho Y and Lee DH: The inhibition of SRC family kinase suppresses pancreatic cancer cell proliferation, migration, and invasion. Pancreas. 43:768–776. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Saini S, Majid S, Shahryari V, et al: Regulation of SRC Kinases by microRNA-3607 located in a frequently deleted locus in prostate cancer. Mol Cancer Ther. 13:1952–1963. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Balkwill F: The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol. 14:171–179. 2004. View Article : Google Scholar : PubMed/NCBI

33 

Kulbe H, Levinson NR, Balkwill F and Wilson JL: The chemokine network in cancer - much more than directing cell movement. Int J Dev Biol. 48:489–496. 2004. View Article : Google Scholar : PubMed/NCBI

34 

Bjorge JD, Pang A and Fujita DJ: Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. J Biol Chem. 275:41439–41446. 2000. View Article : Google Scholar : PubMed/NCBI

35 

Dehm SM and Bonham K: SRC gene expression in human cancer: the role of transcriptional activation. Biochem Cell Biol. 82:263–274. 2004. View Article : Google Scholar : PubMed/NCBI

36 

Mirmohammadsadegh A, Hassan M, Bardenheuer W, et al: STAT5 phosphorylation in malignant melanoma is important for survival and is mediated through SRC and JAK1 kinases. J Invest Dermatol. 126:2272–2280. 2006. View Article : Google Scholar : PubMed/NCBI

37 

Niu G, Bowman T, Huang M, et al: Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene. 21:7001–7010. 2002. View Article : Google Scholar : PubMed/NCBI

38 

Song L, Morris M, Bagui T, Lee FY, Jove R and Haura EB: Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res. 66:5542–5548. 2006. View Article : Google Scholar : PubMed/NCBI

39 

Chen Z, Lee FY, Bhalla KN and Wu J: Potent inhibition of platelet-derived growth factor-induced responses in vascular smooth muscle cells by BMS-354825 (dasatinib). Mol Pharmacol. 69:1527–1533. 2006. View Article : Google Scholar : PubMed/NCBI

40 

Schittenhelm MM, Shiraga S, Schroeder A, et al: Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 66:473–481. 2006. View Article : Google Scholar : PubMed/NCBI

41 

Nakata Y, Tomkowicz B, Gewirtz AM and Ptasznik A: Integrin inhibition through Lyn-dependent cross talk from CXCR4 chemokine receptors in normal human CD34+ marrow cells. Blood. 107:4234–4239. 2006. View Article : Google Scholar : PubMed/NCBI

42 

Chen YY, Malik M, Tomkowicz BE, Collman RG and Ptasznik A: BCR-ABL1 alters SDF-1alpha-mediated adhesive responses through the beta2 integrin LFA-1 in leukemia cells. Blood. 111:5182–5186. 2008. View Article : Google Scholar : PubMed/NCBI

43 

Smolinska MJ, Page TH, Urbaniak AM, Mutch BE and Horwood NJ: Hck tyrosine kinase regulates TLR4-induced TNF and IL-6 production via AP-1. J Immunol. 187:6043–6051. 2011. View Article : Google Scholar : PubMed/NCBI

44 

Lutz MP, Esser IB, Flossmann-Kast BB, et al: Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma. Biochem Biophys Res Commun. 243:503–508. 1998. View Article : Google Scholar : PubMed/NCBI

45 

Shor AC, Keschman EA, Lee FY, et al: Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. Cancer Res. 67:2800–2808. 2007. View Article : Google Scholar : PubMed/NCBI

46 

Michels S, Trautmann M, Sievers E, et al: SRC signaling is crucial in the growth of synovial sarcoma cells. Cancer Res. 73:2518–2528. 2013. View Article : Google Scholar : PubMed/NCBI

47 

Díaz-Montero CM, Wygant JN and McIntyre BW: PI3-K/Akt-mediated anoikis resistance of human osteosarcoma cells requires Src activation. Eur J Cancer. 42:1491–1500. 2006. View Article : Google Scholar : PubMed/NCBI

48 

Villacis RA, Silveira SM, Barros-Filho MC, et al: Gene expression profiling in leiomyosarcomas and undifferentiated pleomorphic sarcomas: SRC as a new diagnostic marker. PLoS One. 9:e1022812014. View Article : Google Scholar : PubMed/NCBI

49 

Bai Y, Li J, Fang B, et al: Phosphoproteomics identifies driver tyrosine kinases in sarcoma cell lines and tumors. Cancer Res. 72:2501–2511. 2012. View Article : Google Scholar : PubMed/NCBI

50 

Geng S, Wang X, Xu X, et al: Steroid receptor co-activator-3 promotes osteosarcoma progression through up-regulation of FoxM1. Tumour Biol. 35:3087–3094. 2014. View Article : Google Scholar : PubMed/NCBI

51 

Scully SP, Layfield LJ and Harrelson JM: Prognostic markers in chondrosarcoma: evaluation of cell proliferation and of regulators of the cell cycle. Sarcoma. 1:79–87. 1997. View Article : Google Scholar : PubMed/NCBI

52 

Watanabe T, Tsuda M, Tanaka S, et al: Adaptor protein Crk induces Src-dependent activation of p38 MAPK in regulation of synovial sarcoma cell proliferation. Mol Cancer Res. 7:1582–1592. 2009. View Article : Google Scholar : PubMed/NCBI

53 

Watanabe T, Tsuda M, Makino Y, et al: Adaptor molecule Crk is required for sustained phosphorylation of Grb2-associated binder 1 and hepatocyte growth factor-induced cell motility of human synovial sarcoma cell lines. Mol Cancer Res. 4:499–510. 2006. View Article : Google Scholar : PubMed/NCBI

54 

Mazzone M and Comoglio PM: The Met pathway: master switch and drug target in cancer progression. FASEB J. 20:1611–1621. 2006. View Article : Google Scholar : PubMed/NCBI

55 

Spreafico A, Schenone S, Serchi T, et al: Antiproliferative and proapoptotic activities of new pyrazolo[3,4-d]pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells. FASEB J. 22:1560–1571. 2008.PubMed/NCBI

56 

Hingorani P, Zhang W, Gorlick R and Kolb EA: Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo. Clin Cancer Res. 15:3416–3422. 2009. View Article : Google Scholar : PubMed/NCBI

57 

Horng CT, Shieh PC, Tan TW, Yang WH and Tang CH: Paeonol suppresses chondrosarcoma metastasis through up-regulation of miR-141 by modulating PKCδ and c-Src signaling pathway. Int J Mol Sci. 15:11760–11772. 2014. View Article : Google Scholar : PubMed/NCBI

58 

Wu CM, Li TM, Tan TW, Fong YC and Tang CH: Berberine Reduces the Metastasis of Chondrosarcoma by Modulating the α v β 3 Integrin and the PKC δ, c-Src, and AP-1 Signaling Pathways. Evid Based Complement Alternat Med. 2013:4231642013.PubMed/NCBI

59 

van Oosterwijk JG, van Ruler MA, Briaire-de Bruijn IH, et al: Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells. Br J Cancer. 109:1214–1222. 2013. View Article : Google Scholar : PubMed/NCBI

60 

Guarino M: Epithelial-mesenchymal transition and tumour invasion. Int J Biochem Cell Biol. 39:2153–2160. 2007. View Article : Google Scholar : PubMed/NCBI

61 

Boyer B, Bourgeois Y and Poupon MF: Src kinase contributes to the metastatic spread of carcinoma cells. Oncogene. 21:2347–2356. 2002. View Article : Google Scholar : PubMed/NCBI

62 

Huang WS, Wang RJ, Ding JL, et al: Caveolin-1: a novel biomarker for prostate cancer. Zhonghua Nan Ke Xue. 18:635–638. 2012.(In Chinese). PubMed/NCBI

63 

Mercier I and Lisanti MP: Caveolin-1 and breast cancer: a new clinical perspective. Adv Exp Med Biol. 729:83–94. 2012.PubMed/NCBI

64 

Cantiani L, Manara MC, Zucchini C, et al: Caveolin-1 reduces osteosarcoma metastases by inhibiting c-Src activity and met signaling. Cancer Res. 67:7675–7685. 2007. View Article : Google Scholar : PubMed/NCBI

65 

Manara MC, Bernard G, Lollini PL, et al: CD99 acts as an oncosuppressor in osteosarcoma. Mol Biol Cell. 17:1910–1921. 2006. View Article : Google Scholar : PubMed/NCBI

66 

Scotlandi K, Zuntini M, Manara MC, et al: CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity. Oncogene. 26:6604–6618. 2007. View Article : Google Scholar : PubMed/NCBI

67 

Abraham J, Chua YX, Glover JM, et al: An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma. Biochem Biophys Res Commun. 426:363–368. 2012. View Article : Google Scholar : PubMed/NCBI

68 

Homsi J, Cubitt C and Daud A: The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets. 11:91–100. 2007. View Article : Google Scholar : PubMed/NCBI

69 

Creedon H and Brunton VG: Src kinase inhibitors: promising cancer therapeutics? Crit Rev Oncog. 17:145–159. 2012. View Article : Google Scholar : PubMed/NCBI

70 

Molina JR, Foster NR, Reungwetwattana T, et al: A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621. Lung Cancer. 85:245–250. 2014. View Article : Google Scholar : PubMed/NCBI

71 

Taylor JW, Dietrich J, Gerstner ER, et al: Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. J Neurooncol. Nov 20–2014.(Epub ahead of print).

72 

Montero JC, Seoane S, Ocaña A and Pandiella A: Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res. 17:5546–5552. 2011. View Article : Google Scholar : PubMed/NCBI

73 

Schrage YM, Briaire-de Bruijn IH, de Miranda NF, et al: Kinome profiling of chondrosarcoma reveals SRC-pathway activity and dasatinib as option for treatment. Cancer Res. 69:6216–6222. 2009. View Article : Google Scholar : PubMed/NCBI

74 

Musumeci F, Schenone S, Brullo C and Botta M: An update on dual Src/Abl inhibitors. Future Med Chem. 4:799–822. 2012. View Article : Google Scholar : PubMed/NCBI

75 

Girotti MR, Lopes F, Preece N, et al: Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma. Cancer Cell. 27:85–96. 2015. View Article : Google Scholar : PubMed/NCBI

76 

Rotert JV, Leupold J, Hohenberger P, Nowak K and Allgayer H: Src activity is increased in gastrointestinal stromal tumors - analysis of associations with clinical and other molecular tumor characteristics. J Surg Oncol. 109:597–605. 2014. View Article : Google Scholar : PubMed/NCBI

77 

Qayyum T, McArdle PA, Lamb GW, et al: Expression and prognostic significance of Src family members in renal clear cell carcinoma. Br J Cancer. 107:856–863. 2012. View Article : Google Scholar : PubMed/NCBI

78 

Sell H, Habich C and Eckel J: Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol. 8:709–716. 2012. View Article : Google Scholar : PubMed/NCBI

79 

Spaeth E, Klopp A, Dembinski J, Andreeff M and Marini F: Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 15:730–738. 2008. View Article : Google Scholar : PubMed/NCBI

80 

Hemmerle T, Probst P, Giovannoni L, Green AJ, Meyer T and Neri D: The antibody-based targeted delivery of TNF in combination with doxorubicin eradicates sarcomas in mice and confers protective immunity. Br J Cancer. 109:1206–1213. 2013. View Article : Google Scholar : PubMed/NCBI

81 

Spitaleri G, Berardi R, Pierantoni C, et al: Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours. J Cancer Res Clin Oncol. 139:447–455. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

July-2015
Volume 10 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
Chen Q, Zhou Z, Shan L, Zeng H, Hua Y and Cai Z: The importance of Src signaling in sarcoma (Review). Oncol Lett 10: 17-22, 2015
APA
Chen, Q., Zhou, Z., Shan, L., Zeng, H., Hua, Y., & Cai, Z. (2015). The importance of Src signaling in sarcoma (Review). Oncology Letters, 10, 17-22. https://doi.org/10.3892/ol.2015.3184
MLA
Chen, Q., Zhou, Z., Shan, L., Zeng, H., Hua, Y., Cai, Z."The importance of Src signaling in sarcoma (Review)". Oncology Letters 10.1 (2015): 17-22.
Chicago
Chen, Q., Zhou, Z., Shan, L., Zeng, H., Hua, Y., Cai, Z."The importance of Src signaling in sarcoma (Review)". Oncology Letters 10, no. 1 (2015): 17-22. https://doi.org/10.3892/ol.2015.3184