P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

Abstract

Breast cancer metastasis to bone is a major contributor to morbidity and mortality in patients and remains an unmet clinical need. Purinergic signalling via the P2X7 receptor (P2RX7) in the primary tumour microenvironment is associated with progression of several cancers. It has also now become evident that intra-tumoural hypoxia facilitates cancer metastasis and reduces patient survival. In this study, we present data suggesting that hypoxia regulates the expression of P2RX7 in the primary tumour microenvironment; and importantly, inhibition with a selective antagonist (10mg/kg A740003) increased cancer cell death via apoptosis in a E0771/C57BL-6J syngeneic murine model. Furthermore, micro-computed tomography demonstrated reduced number of osteolytic lesions and lesion area following P2RX7 inhibition in absence of overt metastases by decreasing osteoclast numbers. We also demonstrate that activation of P2RX7 plays a role in the secretion of extracellular vesicles (EVs) from breast cancer cells. Mass-spectrometric analyses showed a distinct protein signature for EVs derived from hypoxic compared with normoxic cancer cells which elicit specific responses in bone cells that are associated with pre-metastatic niche formation. Thus, inhibiting P2RX7 provides a novel opportunity to preferentially target the hypoxic breast cancer cells preventing tumour progression and subsequent metastasis to bone

Purinergic signaling and purine base metabolism at the crossroads between immunity, metabolism, and cancer: A review

“…140 Given our current understanding of the field of purinergic signaling, adenosine and its receptors are key therapeutic targets. CD73 is an interesting immunotherapy target due to its enzymatic role in generating adenosine from AMP, 141 while adenosine receptors 142,143 and purinoceptors 144 are being interrogated for their impact in tumor responses to both chemotherapies and immunotherapies. However, the focus in the field of purinergic signaling in cancer therapies appears to be shifting in the direction of immunomodulatory agents.…”