CXCR4/ACKR3/CXCL12 axis in the lymphatic metastasis of vulvar squamous cell carcinoma

Abstract

AimsVulvar squamous cell carcinoma (VSCC) spreads early and mainly locally via direct expansion into adjacent structures, followed by lymphatic metastasis to the regional lymph nodes (LNs). In the lymphatic metastasis, cancer cells bearing CXCR4 and ACKR3 (CXCR7) receptors are recruited to the LNs that produce the CXCL12 ligand. Our study aimed to assess the role of the CXCR4/ACKR3/CXCL12 axis in VSCC progression.MethodsTumour and LN tissue samples were obtained from 46 patients with VSCC and 51 patients with premalignant vulvar lesions. We assessed CXCR4, ACKR3 and CXCL12 by immunohistochemistry (IHC) in the tissue samples. Additionally, CXCL12 levels were determined by ELISA in the sera of 23 patients with premalignant lesions, 37 with VSCC and 16 healthy volunteers.ResultsCXCR4 and ACKR3 proteins were virtually absent in vulvar precancers, while in VSCC samples the IHC staining was strong. In the LNs of patients with VSCC, 98% of metastatic cells expressed CXCR4 and 85% expressed ACKR3. Neither CXCR4 nor ACKR3 presence was correlated with tumour human papilloma virus status. Few CXCL12-positive cells were found in the analysed tissue samples, but serum CXCL12 levels were significantly increased in both patients with premalignant vulvar lesions and with VSCC compared with healthy volunteers.ConclusionsIt appears that during progression and lymphatic spread of VSCC, the CXCR4/ACKR3/CXCL12 axis is activated. Moreover, our data suggest that CXCR4 antagonists merit further attention as a possible therapeutic option in patients with VSCC.

Reprogramming of sentinel lymph node microenvironment during tumor metastasis

“…Several paired ligand-receptor pathways, including CXCL12-CXCR4, CCL19-CCR7 and CCL21-CCR7, also effectively promote the lymph node invasion of cancer cells [126][127][128]. These studies imply that the cytokine/chemokine milieu plays a crucial role in establishing a pre-metastatic microenvironment in the SLN.…”

“…Das et al found that CCL1 protein was detected in the lymph node and lymphatic sinuses, and CCR8, the cognate receptor for CCL1, was significantly upregulated on the cell surface of human melanoma cells, providing a molecular basis for how CCL1 promotes cancer cell invasion into the SLN [ 125 ]. Several paired ligand-receptor pathways, including CXCL12-CXCR4, CCL19-CCR7 and CCL21-CCR7, also effectively promote the lymph node invasion of cancer cells [ 126 – 128 ]. These studies imply that the cytokine/chemokine milieu plays a crucial role in establishing a pre-metastatic microenvironment in the SLN.…”

Current Status of 68Ga-Pentixafor in Solid Tumours

“…VSCC spreads predominantly via lymphatic spread, and the presence of inguinal lymph nodes is an independent predictor of survival. Patients with histologically negative inguinal lymph nodes (LNs) have survival rates of 90% vs. 50% for those with histologically positive inguinal LNs [ 58 ].…”

“…Similarly, Rusetska et al also evaluated CXCR4 expression on tumour and lymph node tissue samples obtained from 46 patients with VSCC as well as 51 patients with premalignant vulvar lesions. CXCR4 overexpression was noted in VSCC samples and none in vulvar precancers; additionally, 98% of the metastatic LNs of patients with VSCC expressed CXCR4 [ 58 ]. Again, in vulvar carcinoma, CXCR4-targeted imaging could potentially be used to prognosticate patients as well as to select patients who may benefit from therapies targeting CXCR4.…”