CXCR‐4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells

Sehgal, Anil; Keener, Cassie L.; Boynton, Alton L.; Warrick, Jami; Murphy, Gerald P.

doi:10.1002/(sici)1096-9098(199810)69:2<99::aid-jso10>3.3.co;2-d

Cited by 18 publications

(17 citation statements)

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“…[14][15][16][17][18][19][20][21][22] CXCR4 expression by cancer cells may also correlate with disease severity. For instance, Muller et al showed that normal breast tissues express low amounts of CXCR4, whereas breast neoplastic tissues express high levels of CXCR4.…”

Section: Cxcr4-mediated Pca Migration and Invasion S Singh Et Alsupporting

confidence: 92%

CXCL12–CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion

Singh

Grizzle

et al. 2004

Laboratory Investigation

213

187

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The mechanisms responsible for prostate cancer metastasis are incompletely understood at both the cellular and molecular levels. In this regard, chemokines are a family of small, cytokine-like proteins that induce motility of neoplastic cells, leukocytes and cancer cells. The current study evaluates the molecular mechanisms of CXCL12 and CXCR4 in prostate cancer cell migration and invasion. We report that functional CXCR4 is significantly expressed by prostate cancer cell lines, LNCaP and PC3, when compared with normal prostatic epithelial cells (PrEC). As measured using motility and invasion chamber assays, prostate cancer cells migrated and invaded through extracellular matrix components in response to CXCL12, at rates that corresponded to CXCR4 expression. Anti-CXCR4 antibodies (Abs) significantly impaired the migration and invasive potential of PC3 and LNCaP cells. CXCL12 induction also enhanced collagenase-1 (metalloproteinase-1 (MMP-1)) expression by LNCaP and PC3 cells. Collagenase-3 (MMP-13) was expressed by prostate cancer cells, but it was not expressed by PrEC cells or modulated by CXCL12. CXCL12 increased MMP-2 expression by LNCaP and PC3; however, MMP-9 expression was elevated only in PC3 cells after CXCL12-CXCR4 ligation. PC3 cells also expressed high levels of stromelysin-1 (MMP-3) after CXCL12 stimulation. CXCL12 also significantly Keywords: chemokine; metastasis; metalloproteinase; stromal cell-derived factor-1; SDF-1 Despite the obvious importance of metastasis, this process remains incompletely understood at both the cellular and molecular levels. 1 Many factors have been implicated in the process of metastasis, but the precise mechanisms for the directional migration of malignant cells into different organs is unknown. [2][3][4] In this regard, chemokines are a super family of small, cytokine-like proteins that inducethrough G-protein-coupled receptor and cytoskeletal rearrangement-the adhesion of neoplastic cells or leukocytes to endothelial cells as well as the directional migration of cancer cells. 5,6 The ability of neoplastic cells to penetrate the basement membrane and then invade the interstitial stroma to initiate the metastatic process is largely mediated by proteolysis. Many proteinases are capable of degrading extracellular matrix (ECM) components, but matrix metalloproteinases (MMPs) appear to be particularly important for matrix degradation. 6 These proteolytic enzymes are involved in connective tissue remodeling as well as in embryonic growth, ovulation, wound healing and menstruation. 7,8 Moreover, abnormal production of these proteinases is implicated in a number of pathological conditions. 9 It has been shown that CXCL12-CXCR4 interactions may play a role in the metastasis of prostate cancer to bone. 10 However, these interactions alone do not explain the metastasis pattern of prostate cancer or the potential for neoplastic prostate cells to migrate and invade other tissues. We have tested the hypothesis that prostate carcinomas use CXCR4-

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Section: Cxcr4-mediated Pca Migration and Invasion S Singh Et Alsupporting

confidence: 92%

CXCL12–CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion

Singh

Grizzle

et al. 2004

Laboratory Investigation

213

187

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“…Predominant CXCR4 vs. other CKR expression on long-term cell lines and cancers has led to the CXCR4-CXCL12 (SDF-1) ''oncogenic axis'' concept. [1][2][3][4][5][6] Most studies implicate CXCR4 in metastatic invasiveness, rather than proliferation and transformation, but there is evidence for transformation-related signaling, allowing proliferating cells to escape apoptotic control. 4 Thus, in the absence of other CKRs, CXCR4 mediated antiapoptotic Akt phosphorylation in response to SDF-1 on 13 of 16 glioma lines.…”

supporting

confidence: 92%

“…4 Thus, in the absence of other CKRs, CXCR4 mediated antiapoptotic Akt phosphorylation in response to SDF-1 on 13 of 16 glioma lines. 5,6 Also, stimulation with a-CD28 þ a-CD3 þ interleukin (IL)-2 reversibly blocked T cell surface expression of CCR5, but not CXCR4, and allowed continuous exponential growth. 7 Although not previously emphasized, this is the best published in vitro evidence of dichotomous roles for these two CKRs in apoptosis.…”

mentioning

confidence: 99%

Potentiation of EBV-Induced B Cell Transformation by CXCR4-Tropic, But Not CCR5-Tropic, HIV gp120: Implications for HIV-Associated Lymphomagenesis

Iyengar

Schwartz

2011

AIDS Research and Human Retroviruses

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R5 and X4 HIV strains use CCR5 or CXCR4 chemokine receptors (CKRs), respectively, for entry. Preferential growth of X4 vs. R5 HIV in cell lines reflects constitutive expression of CXCR4, but not CCR5 (in contrast to dual expression on primary T cells), and CXCR4 is the predominant CKR found on most tumors. Non-Hodgkin's B cell lymphomas (NHL) are increased among HIV þ patients, and interactions between HIV envelope and CKRs may contribute to lymphomagenesis. Despite strong evidence for a CXCR4-SDF-1 oncogenic axis, no in vitro evaluation of CXCR4-mediated normal lymphocyte transformation has been published. Exposure of normal B cells to EBV in the presence of X4 gp120 (but not R5 gp120) increased proliferation and BLCL outgrowth, comparable to anti-CD40 mAb costimulation. This suggests a role for X4 tropic viral envelope signaling via CXCR4 and/or CXCR7 in HIV-associated lymphomagenesis.

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“…We analysed anchorage-independent growth in a soft agar assay (Missale et al, 1998), where cells proliferate without cell or surface contacts and must overcome contact inhibition. Consistently with reports on other malignancies (Sehgal et al, 1998;Huang et al, 2005), we demonstrate a complete inhibition of soft agar proliferation in the cell lines NCI-H69 and NCI-H82 by blocking JAK2 or CXCR4 with the inhibitors AG490 and TN14003, respectively.…”

Section: Discussionmentioning

confidence: 99%

Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

et al. 2009

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Small cell lung cancer (SCLC) is an aggressive, rapidly metastasising tumour. Previously, we demonstrated the influence of CXCL12 -CXCR4 interaction on processes involved in metastasis and chemoresistance in SCLC. We show here that STAT3 is expressed in both primary SCLC tumour tissues and SCLC cell lines. We investigated the function of STAT3 upon CXCL12 stimulation in SCLC cell lines. Small cell lung cancer cell lines present constitutive phosphorylation of STAT3, and in the reference cell lines NCI-H69 and NCI-H82 constitutive phosphorylation was further increased by CXCL12 stimulation. Further investigating this signalling cascade, we showed that it involves interactions between CXCR4 and JAK2 in both cell lines. However CXCL12-induced adhesion to VCAM-1 could be completely inhibited by the JAK2 inhibitor AG490 only in NCI-H82. Furthermore, CXCR4 antagonist but not AG490 inhibited cell adhesion whereas both antagonisms were shown to inhibit growth of the cells in soft agar, indicating the central involvement of this signalling in anchorage-independent growth of SCLC cells. Most interestingly, while using primary tumour material, we observed that in contrast to non-small-cell lung cancer samples from primary tumour tissues, all analysed samples from SCLC were strongly positive for tyrosine-phosphorylated STAT3. Taken together, these data indicate that STAT3 is constitutively phosphorylated in SCLC and is important in SCLC growth and spreading thus presenting an interesting target for therapy.

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CXCR‐4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells

Cited by 18 publications

References 0 publications

CXCL12–CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion

CXCL12–CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion

Potentiation of EBV-Induced B Cell Transformation by CXCR4-Tropic, But Not CCR5-Tropic, HIV gp120: Implications for HIV-Associated Lymphomagenesis

Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

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