Chemosensitization of prostate cancer stem cells in mice by angiogenin and plexin-B2 inhibitors

Abstract

Cancer stem cells (CSCs) are an obstacle in cancer therapy and are a major cause of drug resistance, cancer recurrence, and metastasis. Available treatments, targeting proliferating cancer cells, are not effective in eliminating quiescent CSCs. Identification of CSC regulators will help design therapeutic strategies to sensitize drug-resistant CSCs for chemoeradication. Here, we show that angiogenin and plexin-B2 regulate the stemness of prostate CSCs, and that inhibitors of angiogenin/plexin-B2 sensitize prostate CSCs to chemotherapy. Prostate CSCs capable of self-renewal, differentiation, and tumor initiation with a single cell inoculation were identified and shown to be regulated by angiogenin/plexin-B2 that promotes quiescence and self-renewal through 5S ribosomal RNA processing and generation of the bioactive 3′-end fragments of 5S ribosomal RNA, which suppress protein translation and restrict cell cycling. Monoclonal antibodies of angiogenin and plexin-B2 decrease the stemness of prostate CSCs and sensitize them to chemotherapeutic agents in vitro and in vivo.

Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis

“…Particularly, ANG stimulates endothelial cell growth and proliferation, mainly by promoting 47S rRNA transcription [60][61][62] . Recently, plexin-B2 (PLXNB2), a transmembrane receptor belonging to the large family of plexin proteins, was identified as a functional ANG receptor that is both necessary and sufficient for the physiological and pathological functions of ANG in multiple cell types, including endothelial, cancer, neuronal, normal hematopoietic and leukemic stem and progenitor cells, as well as intestinal epithelial cells 63,64 . Upon secretion, ANG is endocytosed in target cells via PLXNB2 62,65 and accumulates in the nucleus, where it regulates rRNA transcription to promote cell proliferation 61,[66][67][68][69] .…”

A monoclonal antibody against annexin A2 targets stem and progenitor cell fractions in tumors

“…AnxA2 is reported to be co-expressed with CSC markers including DCLK1, LGR5, and CD44 on circulating CSCs in clinical samples [43] , suggesting AnxA2 expression in these populations made them vulnerable to mAb150 neutralizing activity. A similar mechanism was recently validated in prostate tumors where mAbs for angiogenin and plexin-B2 sensitized CSCs for chemotherapy by diminishing their stemness features [44] . Such sensitization could drive exhaustion of the CSC-progenitor repertoire in xenografts, which reflects on the ability of mAb150 to perturb tumor heterogeneity by targeting regenerative sub-populations in tumors.…”

Plexin-B3 Regulates Cellular Motility, Invasiveness, and Metastasis in Pancreatic Cancer

“…Many recent reports have revealed that axon guidance cue molecules like the semaphorin/plexin axis are hijacked by different cancer cells to aid in their growth, differentiation, and renewal of cancer stem-like cells [ 31 , 32 , 33 , 34 ]. Our interest in investigating the role of Plexin-B3 in stem cell properties of PC cells came from various studies that demonstrate Plexin-B’s role in regulating the stemness of different cancers [ 30 , 35 , 36 , 37 ]. We examined two cancer stem cell markers: ALDH1-A1 and CD44 in the tumors and observed an increase in ALDH1-A1-positive cells in tumors compared to Plexin-B3 knockdown cells, suggesting that the loss of Plexin-B3 may directly or indirectly check cell proliferation and enhance cancer stemness in PC malignancy.…”