ArticleCancer cell international2026
Targeting the CCL5/CCR5-PI3K-AKT axis suppresses hepatic stellate cell-induced breast cancer metastasis.
Article in Cancer cell international, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Abstract
backgroundBreast cancer liver metastasis is a major contributor to cancer-related death; however, the function of hepatic stellate cells (HSCs) in shaping the metastatic microenvironment remains poorly understood. This study investigates how HSC-secreted CCL5 activates the PI3K-AKT pathway via CCR5 to drive breast cancer invasion and metastasis.
methodsIn vitro co-culture models of HSCs with MDA-MB-231 and MCF-7 cells were employed, alongside Transwell migration/invasion assays. Conditioned medium (CM) from activated HSCs was used to assess tumor cell behavior. CCR5 and PI3K-AKT inhibitors (Maraviroc, BKM120) and siRNA-mediated gene silencing were applied to dissect molecular mechanisms. In vivo models, including liver metastasis assays and xenografts using CM-pretreated breast cancer cells, evaluated tumor colonization and growth. Bioinformatics analysis of TCGA data correlated CCL5 expression with clinical outcomes.
resultsBreast cancer cells induced the activation of HSCs, triggering the secretion of CCL5. This HSC-derived CCL5 significantly enhanced tumor cell growth, motility, invasiveness, and epithelial-mesenchymal transition (EMT) by binding to CCR5 and activating the PI3K-AKT pathway. Conversely, silencing CCL5 in HSCs or CCR5 in tumor cells suppressed these malignant behaviors and inhibited PI3K-AKT phosphorylation. In vivo, blocking this axis attenuated tumor growth and liver metastasis. Notably, the anti-tumor effects of CCR5 inhibition were reversed by the PI3K activator 740 Y-P, confirming mechanism specificity. Clinical analysis revealed that elevated CCL5 expression correlates with poor prognosis in breast cancer patients.
conclusionsThis study identifies a critical stromal-tumor signaling loop where the HSC-CCL5/CCR5 axis drives breast cancer metastasis via PI3K-AKT-dependent EMT. Targeting this crosstalk represents a promising therapeutic strategy for preventing liver metastasis.
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