Herein, taking the amide-sulfamide as the lead structure, the second-round structural modifications to the sulfamide structure were performed to obtain more active CXCR4 modulators against tumor metastasis.
Overall, 412 samples from 165 GEP-NEN patients, comprising both primary tumors (PT) and metastases (MTS), originating from different parts of the gastrointestinal tract or the pancreas were evaluated for SST and CXCR4 expression by means of immunohistochemistry using monoclonal antibodies.
CXCR4-mediated uptake was assessed both visually and semi-quantitatively by evaluation of maximum standardized uptake values (SUV<sub>max</sub>) of both primary tumors and metastases.
Altogether, our study identifies a novel cross-talk between PI4KIIIα and CXCR4 in promoting tumor metastasis and suggests that PI4KIIIα pharmacological targeting may have therapeutic benefit for advanced prostate cancer patients.
The knockdown of AIB1 greatly reduced CXCR4 gene expression at both the transcription and protein levels, whereas the knockdown of CXCR4 in cells with AIB1 ectopic overexpression diminished AIB1-induced migration and invasion in vitro and tumor metastasis in vivo.
Correction: Screening of cancer tissue arrays identifies CXCR4 on adrenocortical carcinoma: correlates with expression and quantification on metastases using <sup>64</sup>Cu-plerixafor PET.
Another factor explaining the osteotropism of CSCs is their ability to recognize chemokine gradients toward BM, through the CXCL12-CXCR4 axis, also known to be involved in tumor metastasis to other organs.
CXCR4 was more expressed in PT than in metastases (p = 0.0067), whereas CXCL12 was highly expressed in metastatic lesions located in liver and lung (p < 0.0001), as reported for human breast cancer.
Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing.
The CXCL12/CXCR4 pathway can influence RT response by recruiting normal myeloid cells to the tumor microenvironment that in turn can exert radioprotective effects, and may promote metastases.
Recent exploration of combination therapies with CXCR4 antagonists have demonstrated improved outcomes, and abolishing the contribution of this pathway may prove crucial to effectively treat pancreatic cancer at both the primary tumor and metastases.
These studies indicated critical roles for CXCR4 and CXCR7 mediation of tumor metastasis in several types of cancers, suggesting their contributions as biomarkers of tumor behavior as well as potential therapeutic targets.