Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies

Peled, Amnon; Klein, Shoshana; Beider, Katia; Burger, Jan A.; Abraham, Michal

doi:10.1016/j.cyto.2018.02.020

Cited by 71 publications

(75 citation statements)

References 80 publications

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“…Altogether, the poor response to CXCR4 antagonism in AML is consistent with disappointing results from clinical studies and uncertainty about the group of patients that would benefit from this treatment strategy. 13 While it has been proposed that stronger inhibitors than AMD3100 may improve treatment outcome, 22,23 our study suggests that the limited effectiveness of CXCR4 antagonists in AML might be partially explained by its mode of action being limited to blast mobilization, while lacking an effect on the behavior of parenchymal AML. This is consistent with the unsatisfactory results obtained by combining CXCR4 inhibition with further mobilization through G-CSF.…”

Section: Discussionmentioning

confidence: 73%

“…CXCR4 antagonists in combination with chemotherapy have been tested in phase 1/2 clinical trials in relapsed and refractory AML (reviewed in Cho et al . and Peled et al …”

Section: Introductionmentioning

confidence: 99%

“…7 CXCR4 inhibition prolongs the survival of T-ALL burdened mice, 8 and promotes mobilization and apoptosis of AML cells. [9][10][11] CXCR4 antagonists in combination with chemotherapy have been tested in phase 1/2 clinical trials in relapsed and refractory AML (reviewed in Cho et al 12 and Peled et al 13 ). These studies suggest that inhibiting CXCR4 might form an important arm of future therapeutic approaches for blood cancer of specific lineages.…”

Section: Introductionmentioning

confidence: 99%

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Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging

et al. 2018

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The majority of acute myeloid leukemia ( AML ) patients have a poor response to conventional chemotherapy. The survival of chemoresistant cells is thought to depend on leukemia‐bone marrow ( BM ) microenvironment interactions, which are not well understood. The CXCL 12/ CXCR 4 axis has been proposed to support AML growth but was not studied at the single AML cell level. We recently showed that T‐cell acute lymphoblastic leukemia (T‐ ALL ) cells are highly motile in the BM ; however, the characteristics of AML cell migration within the BM remain undefined. Here, we characterize the in vivo migratory behavior of AML cells and their response to chemotherapy and CXCR 4 antagonism, using high‐resolution 2‐photon and confocal intravital microscopy of mouse calvarium BM and the well‐established MLL ‐ AF 9‐driven AML mouse model. We used the Notch1‐driven T‐ ALL model as a benchmark comparison and AMD 3100 for CXCR 4 antagonism experiments. We show that AML cells are migratory, and in contrast with T‐ ALL , chemoresistant AML cells become less motile. Moreover, and in contrast with T‐ ALL , the in vivo exploratory behavior of expanding and chemoresistant AML cells is unaffected by AMD 3100. These results expand our understanding of AML cells‐ BM microenvironment interactions, highlighting unique traits of leukemia of different lineages.

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Section: Discussionmentioning

confidence: 73%

“…CXCR4 antagonists in combination with chemotherapy have been tested in phase 1/2 clinical trials in relapsed and refractory AML (reviewed in Cho et al . and Peled et al …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging

et al. 2018

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“…Therefore, CXCR4 + tumor stem cells can migrate or invade along the SDF‐1 concentration gradient to seed in distant tissues or organs. CXCR4 has also been reported to promote the progression of tumors, and the overexpression of CXCR4 has been proved to correlated with poorer prognosis and shorter survival time 37 . Besides, the link between inflammation and cancer, as well as the role CXCR4 plays in the transformation between the two sides, has drawn great attention of oncological researchers.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Chen

Zhou

et al. 2020

Molecular Carcinogenesis

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Brain metastasis is a leading cause of death worldwide, but the mechanism involved remains unclear. Stromal cell‐derived factor‐1 (SDF‐1)/C‐X‐C motif chemokine receptor 4 (CXCR4) signaling has been reported to induce the directed metastasis of cancers, and adenosine A2A receptor activation suppresses the SDF‐1/CXCR4 interaction. However, whether A2A receptor activation implicates the SDF‐1/CXCR4 signaling pathway and thus modulates brain metastasis remains unclear. In this study, Western blot was performed to evaluate the protein levels. Cell invasion and migration assays were used to estimate the metastasis ability of PC‐9 cells. The viability of cells was demonstrated by lactate dehydrogenase and cell proliferation assays. And the findings in vitro were further identified in nude mice. Notably, adenosine A2A receptor activation inhibited the proliferation and viability of PC‐9 cells and thus suppressed the brain metastasis. A2A receptor stimulation protected the function of blood‐brain barrier (BBB). The suppression of brain metastasis and the protection of BBB by A2A receptor relied on SDF‐1/CXCR4 signaling, and treatment using A2A receptor agonist and CXCR4 antagonist protected the nude mice from malignancy metastasis in vivo. Adenosine A2A receptor activation suppressed the brain metastasis by implicating the SDF‐1/CXCR4 axis and protecting the BBB.

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“…12 Specifically, CXCL12 is known to drive lymphocyte and macrophage chemotaxis 13,14 in pathophysiological settings of several systems. 15,[17][18][19][20][21][22][23][24][25][26][27] A gradient of CXCL12 is established by secretion from inflammatory environments. This process is known to promote tumour growth and metastasis in at least 20 malignancies.…”

Section: Xcl12mentioning

confidence: 99%

The CXL12/CXCR4/CXCR7 axis in female reproductive tract disease: Review

Krikun

2018

American J Rep Immunol

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Initial studies on the chemokine stromal derived factor 1 (now referred to as CXCL12) were proposed to be enhanced in several diseases including those which affect the female reproductive tract. These include endometriosis, Asherman's syndrome, endometrial cancers, and ovarian cancers. Additionally, recent studies from our laboratory suggest that CXCL12 signaling is involved in leiomyomas (fibroids). These diseases present an inflammatory/hypoxic environment which further promotes pathology. At first, studies focused on signaling by CXCL12 via its well-known receptor, CXCR4. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in endometrial disease and cancer progression has questioned the potential of "selective blockade"' of CXCR4 to treat these ailments. This review will focus on the signaling and effects of the potent chemokine CXCL12, and its long-known G protein-coupled receptor CXCR4, as well as the alternate receptor CXCR7 on the female reproductive tract and related diseases such as endometriosis, Asherman's syndrome, leiomyomas, endometrial cancer, and ovarian cancer. Although several other mechanisms are inherent to these diseases such as gene mutations, differential expression of miRNAs and epigenetics, for this review, we will focus on the CXCL12/CXCR4/CXCR7 axis as a novel target.

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Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies

Cited by 71 publications

References 80 publications

Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging

Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

The CXL12/CXCR4/CXCR7 axis in female reproductive tract disease: Review

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