Dr. Weeks’ Comment: Increasingly, everyone involved in cancer care is learning to focus on the really important target – the cancer STEM cell – which practitioners of Corrective Cancer Care™ have focused on all along. So how to cancer STEM cells arise? They start out as healthy helpful STEM cells which are recruited by IL6 inflammatory cytokines (an SOS message from injured cancer tissue) are lured to the dark side because of inflammation so by stopping inflammation, we stop recruitment and conversion of helpful STEM cells to lethal cancer STEM cells. So read the article below knowing that the remedy is safe and effective anti-inflammation – such as SOUL and CORE.
Tumors are composed of both cancer stem-like cells (CSCs) and differentiated cancer cells. Each CSC can undergo either a symmetric cell division to produce two CSCs or an asymmetric cell division to produce one CSC and one differentiated cancer cell. It is believed that the rate of symmetric division increases as more CSCs become malignant; however, underlying molecular mechanisms remain elusive. Here we show that stimulation with a cytokine, semaphorin (Sema), activates monooxygenase of MICAL3, a cytoplasmic signal transducer, through the neuropilin (NP) receptor that is specifically expressed on the breast CSC plasma membrane. The activation of MICAL3 induces symmetric division of CSCs. Each molecule in this signaling pathway represents a promising therapeutic target for eliminating CSCs.
Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.
In the current study, we discovered that the Sema3/NP1/MICAL3/CRMP2/Numb axis may be a specific mechanism for the maintenance of the symmetric division of self-renewing CSCs. To the best of our knowledge, this report shows that CSCs and neuronal cells utilize common signaling components for the maintenance of symmetric cell division and for repulsion cues or axonal growth, respectively. It is possible that the Sema3/NP1/MICAL3/CRMP2/Numb axis is active in a portion of the population in any subtype of breast cancer. Breast cancer patients with NP1high staining in tumor tissues showed poor prognosis, and colocalization of Numb in breast cancer tissue samples from these patients was observed, consistent with the notion that NP1high CSCs are responsible for relapse or drug resistance.