Reduced Glioma Infiltration in Src-deficient Mice

Lund, Caren V.; Nguyen, Mai; Owens, Geoffrey C.; Pakchoian, Andrew J.; Shaterian, Ashkaun; Kruse, Carol A.; Eliceiri, Brian P.

doi:10.1007/s11060-005-9068-y

Cited by 49 publications

(49 citation statements)

References 75 publications

(86 reference statements)

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“…The importance of Src family members' activity for glioma infiltration is further supported by their elevated levels in Grade IV glioblastomas compared with healthy brain tissues (Stettner et al, 2005). Furthermore, other authors have demonstrated that orthotopic invasion of gliomas is impaired in c-Src deficient mice (Lund et al, 2006). Our findings that JAM-C and JAM-B are both abnormally expressed by human gliomas and their interaction leads to rapid increase in intracellular levels of activated c-Src may represent a new additional mechanism to boost cSrc-induced glioma motility and invasion.…”

Section: Discussionmentioning

confidence: 95%

Cooperative expression of junctional adhesion molecule‐C and ‐B supports growth and invasion of glioma

Tenan

Aurrand-Lions²,

Widmer

et al. 2009

Glia

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Brain invasion is a biological hallmark of glioma that contributes to its aggressiveness and limits the potential of surgery and irradiation. Deregulated expression of adhesion molecules on glioma cells is thought to contribute to this process. Junctional adhesion molecules (JAMs) include several IgSF members involved in leukocyte trafficking, angiogenesis, and cell polarity. They are expressed mainly by endothelial cells, white blood cells, and platelets. Here, we report JAM-C expression by human gliomas, but not by their normal cellular counterpart. This expression correlates with the expression of genes involved in cytoskeleton remodeling and cell migration. These genes, identified by a transcriptomic approach, include poliovirus receptor and cystein-rich 61, both known to promote glioma invasion, as well as actin filament associated protein, a c-Src binding partner. Gliomas also aberrantly express JAM-B, a high affinity JAM-C ligand. Their interaction activates the c-Src proto-oncogene, a central upstream molecule in the pathways regulating cell migration and invasion. In the tumor microenvironment, this co-expression may thus promote glioma invasion through paracrine stimuli from both tumor cells and endothelial cells. Accordingly, JAM-C/B blocking antibodies impair in vivo glioma growth and invasion, highlighting the potential of JAM-C and JAM-B as new targets for the treatment of human gliomas.

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Section: Discussionmentioning

confidence: 95%

Cooperative expression of junctional adhesion molecule‐C and ‐B supports growth and invasion of glioma

Tenan

Aurrand-Lions²,

Widmer

et al. 2009

Glia

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“…Only in U-87 cells, we observed an upregulation of the double-strand break marker gH2AX and a significant reduction in clonal growth in association with radiotherapy. Interestingly, it was demonstrated that PDGF overexpression in brain tissue determines the activation of an aggressive phenotype mainly in association with SRC (15). In addition, imatinib, an inhibitor of PDGF has demonstrated radiosensitizing activity (16).…”

Section: Discussionmentioning

confidence: 99%

Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells

Calgani

Vignaroli

Zamperini

et al. 2016

Molecular Cancer Therapeutics

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Glioblastoma cells efficiently interact with and infiltrate the surrounding normal tissue, rendering surgical resection and adjuvant chemo/radiotherapy ineffective. New therapeutic targets, able to interfere with glioblastoma's capacity to synergize with normal brain tissue, are currently under investigation. The compound Si306, a pyrazolo[3,4-d]pyrimidine derivative, selected for its favorable activity against SRC, was tested in vitro and in vivo on glioblastoma cell lines. In vivo, combination treatment with Si306 and radiotherapy was strongly active in reducing U-87 xenograft growth with respect to control and single treatments. The histology revealed a significant difference in the stromal compartment of tumoral tissue derived from control or radiotherapy-treated samples with respect to Si306-treated samples, showing in the latter a reduced presence of collagen and a-SMA-positive cells. This effect was paralleled in vitro by the capacity of Si306 to interfere with myofibroblastic differentiation of normal fibroblasts induced by U-87 cells. In the presence of Si306, TGF-b released by U-87 cells, mainly in hypoxia, was ineffective in upregulating a-SMA and b-PDGFR in fibroblasts. Si306 efficiently reached the brain and significantly prolonged the survival of mice orthotopically injected with U-87 cells. Drugs that target SRC could represent an effective therapeutic strategy in glioblastoma, able to block positive paracrine loop with stromal cells based on the b-PDGFR axis and the formation of a tumor-promoting microenvironment. This approach could be important in combination with conventional treatments in the effort to reduce tumor resistance to therapy. Mol Cancer Ther; 15(7); 1535-44. Ó2016 AACR.

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“…Targeted deletion of src in mice reduced glioma cell invasion [26] . GBM is locally invasive, and high expression of genes upregulating invasion correlated with poor prognosis [27] .…”

Section: Non-receptor Tyrosine Kinasesmentioning

confidence: 99%

Targeting multiple kinases in glioblastoma multiforme

Sathornsumetee

Reardon

2009

Expert Opinion on Investigational Drugs

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Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is associated with high mortality. Current standard-of-care treatments, including surgery, radiation and chemotherapy, offer only palliation. Recent research in cancer therapy has shifted towards targeting the specific molecular aberrations that underlie the pathogenesis of cancers including GBM. Protein kinases are a family of enzymes that are key components in regulating cellular homeostasis. Protein kinases can be deregulated by several mechanisms, which contribute to cancer initiation and maintenance. Several protein kinases are important in gliomagenesis, thus representing new therapeutic targets in GBM. Low molecular weight inhibitors are the most commonly used agents to target protein kinases in the treatment of cancers. However, first-generation kinase inhibitors targeting only single kinases have demonstrated limited efficacy in unselected GBM patient populations. Several mechanisms of failure of monotherapy with single-targeted kinase inhibitors have been explained as new therapeutic strategies have emerged to overcome resistance. Simultaneous disruption of several kinases can be achieved by either multitargeted kinase inhibitors or combination of single-targeted kinase inhibitors with one another or with traditional cytotoxics. In this review, we will discuss the current clinical status of targeted therapy in GBM and recent approaches to target multiple kinases in this devastating cancer.

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Reduced Glioma Infiltration in Src-deficient Mice

Cited by 49 publications

References 75 publications

Cooperative expression of junctional adhesion molecule‐C and ‐B supports growth and invasion of glioma

Cooperative expression of junctional adhesion molecule‐C and ‐B supports growth and invasion of glioma

Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells

Targeting multiple kinases in glioblastoma multiforme

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