Expansion of cancer stem cell pool initiates lung cancer recurrence before angiogenesis
Menée à l'aide de modèles murins de cancer du poumon, cette étude met en évidence des mécanismes par lesquels, en induisant la prolifération de cellules souches cancéreuses préalablement à une angiogenèse, le facteur de croissance IGF1 favorise la récidive d'une tumeur
Latent tumor cells are the crucial reason of tumor recurrence and the death of cancer patients. Preventing latent tumor relapse can prolong patients’ survival and have a long time surviving with latent tumor cells. Here, we describe a lung cancer suspensive tumor model in mouse and find that a high level of cancer stem cells undergoing asymmetric cell division in latent tumor is the key issue to reactivate a suspensive tumor. The results clearly delineate the state of latent tumor in vivo. A high level of serum IGF-1 can induce the suspensive-to-progressive tumor transition though promoting CSCs symmetric division, which illuminate a key checkpoint of cancer relapse before angiogenesis, highlighting a potential therapeutic target for preventing tumor recurrence. Angiogenesis is essential in the early stage of solid tumor recurrence, but how a suspensive tumor is reactivated before angiogenesis is mostly unknown. Herein, we stumble across an interesting phenomenon that s.c. xenografting human lung cancer tissues can awaken the s.c. suspensive tumor in nude mice. We further found that a high level of insulin-like growth factor 1 (IGF1) was mainly responsible for triggering the transition from suspensive tumor to progressive tumor in this model. The s.c. suspensive tumor is characterized with growth arrest, avascularity, and a steady-state level of proliferating and apoptotic cells. Intriguingly, CD133+ lung cancer stem cells (LCSCs) are highly enriched in suspensive tumor compared with progressive tumor. Mechanistically, high IGF1 initiates LCSCs self-renewal from asymmetry to symmetry via the activation of a PI3K/Akt/β-catenin axis. Next, the expansion of LCSC pool promotes angiogenesis by increasing the production of CXCL1 and PlGF in CD133+ LCSCs, which results in lung cancer recurrence. Clinically, a high level of serum IGF1 in lung cancer patients after orthotopic lung cancer resection as an unfavorable factor is strongly correlated with the high rate of recurrence and indicates an adverse progression-free survival. Vice versa, blocking IGF1 or CXCL1/PlGF with neutralizing antibodies can prevent the reactivation of a suspensive tumor induced by IGF1 stimulation in the mouse model. Collectively, the expansion of LCSC pool before angiogenesis induced by IGF1 is a key checkpoint during the initiation of cancer relapse, and targeting serum IGF1 may be a promising treatment for preventing recurrence in lung cancer patients.