Expansion of cancer stem cell pool initiates lung cancer recurrence before angiogenesis.

Abstract

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.

• Authors: Lei Li, Jiang-Chao Li, Hong Yang, Xu Zhang, Lu-Lu Liu, Yan Li, Ting-Ting Zeng, Ying-Hui Zhu, Xiao-Dong Li, Yan Li, Dan Xie, Li Fu, Xin-Yuan Guan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 38 Pg. E8948-E8957 (09 18 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 30158168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AC133 Antigen
• CTNNB1 protein, human
• CXCL1 protein, human
• Chemokine CXCL1
• IGF1 protein, human
• PGF protein, human
• PROM1 protein, human
• beta Catenin
• Placenta Growth Factor
• Insulin-Like Growth Factor I
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• AC133 Antigen (metabolism)
• Animals
• Carcinoma, Non-Small-Cell Lung (blood, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Chemokine CXCL1 (antagonists & inhibitors, metabolism)
• Female
• Humans
• Insulin-Like Growth Factor I (analysis, antagonists & inhibitors, metabolism)
• Lung Neoplasms (blood, pathology)
• Mice
• Mice, Nude
• Neoplasm Recurrence, Local (blood, pathology)
• Neoplastic Stem Cells (pathology)
• Neovascularization, Pathologic (blood, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Placenta Growth Factor (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays
• beta Catenin (metabolism)