The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Abstract

In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B‐cell lymphoma

“…57,58 The CXCR4-CXCL12 axis is linked to poor clinical outcomes in DLBCL, 59 and a CXCR4 antagonist has already shown tumor suppressive effects on aggressive B-cell lymphomas in vitro. 60 Ultimately, a better understanding of the tumor microenvironment may be helpful to control the behavior of organotropic invasion in DLBCL.…”

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

“…Whereas gene expression of CD79b, the target of this ADC, is around a median of 7.5 fold-higher in DLBCL patients than non-neoplastic controls, the CXCR4 gene expression, targeted by the T22-AUR nanoconjugate in DLBCL samples is on average 140-fold higher than in normal controls. 10,38 Thus, our nanoconjugate can be targeted more specifically due to the huge CXCR4 overexpression existing in DLBCL patients. 5.…”

“…6,7 Here, we chose the CXCR4 receptor to target lymphoma cells, since around 30-50% of DLBCL biopsies overexpress this receptor (CXCR4 + ) 8,9 and its expression in lymphoma cells is much higher than in normal B cells. 10 Moreover, CXCR4 overexpression is a poor prognostic factor in DLBCL patients. 9,11 Interestingly, microtubule-targeting agents (MTAs) promise to become potent drug-payloads in anticancer treatments.…”

SDF-1 expression after preoperative chemoradiotherapy is associated with prognosis in patients with advanced lower rectal cancer

“…Therefore, SDF-1 might have potential as a new therapeutic target, and could be a useful biomarker for patients with malignant tumors. SDF-1 expression in cancer cells promotes the progression of breast cancer, lung cancer, and lymphoma, and could be a biomarker for a poor prognosis (15)(16)(17). The significance of SDF-1 expression remains unclear, and few reports have focused on SDF-1 expression in advanced lower rectal cancer (18,19).…”