Targeting the Cancer Initiating Cell: The Ultimate Target for Cancer Therapy

James A. McCubrey, Linda S. Steelman, Stephen L. Abrams, Negin Misaghian, William H. Chappell; Jorg Basecke, Ferdinando Nicoletti, Massimo Libra, Giovanni Ligresti, Francac Stivala, Danijela Maksimovic-Ivanic; Sanja Mijatovic, Giuseppeo Montalto, Melchiorre Cervello, Piotr Laidler, Antonio Bonati, Camilla Evangelisti, Lucio Cocco; Alberto M. Martelli

Abstract

An area of therapeutic interest in cancer biology and treatment is targeting the cancer stem cell, more appropriately referred to as the cancer initiating cell (CIC). CICs comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts in genetically modified murine models. CICs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation and metastasis. CICs may lay dormant after various cancer therapies which eliminate the more rapidly proliferating bulk cancer (BC) mass. However, CICs may remerge after therapy is discontinued as they may represent cells which were either intrinsically resistant to the original therapeutic approach or they have acquired mutations which confer resistance to the primary therapy. In experimental mouse tumor transplant models, CICs have the ability to transfer the tumor to immunocompromised mice very efficiently while the BCs are not able to do so as effectively. Often CICs display increased expression of proteins involved in drug resistance and hence they are intrinsically resistant to many chemotherapeutic approaches. Furthermore, the CICs may be in a suspended state of proliferation and not sensitive to common chemotherapeutic and radiological approaches often employed to eliminate the rapidly proliferating BCs. Promising therapeutic approaches include the targeting of certain signal transduction pathways (e.g., RAC, WNT, PI3K, PML) with small molecule inhibitors or targeting specific cell-surface molecules (e.g., CD44), with effective cytotoxic antibodies. The existence of CICs could explain the high frequency of relapse and resistance to many currently used cancer therapies. New approaches should be developed to effectively target the CIC which could vastly improve cancer therapies and outcomes. This review will discuss recent concepts of targeting CICs in certain leukemia models

Keywords: Therapeutic sensitivity, targeted therapy, PI3K, PTEN, Akt, mTOR, radiological, xenografts, chemotherapeutic, germinal mutation