Abstract
The cancer stem cell (CSC) theory predicts that a small fraction of cancer cells possess unique self-renewal activity and mediate tumor initiation and propagation. However, the molecular mechanisms involved in CSC regulation remains unclear, impinging on effective targeting of CSCs in cancer therapy. Here we have investigated the hypothesis that Rac1, a Rho GTPase implicated in cancer cell proliferation and invasion, is critical for tumor initiation and metastasis of human non-small cell lung adenocarcinoma (NSCLA). Rac1 knockdown by shRNA suppressed the tumorigenic activities of human NSCLA cell lines and primary patient NSCLA specimens, including effects on invasion, proliferation, anchorage-independent growth, sphere formation and lung colonization. Isolated side population (SP) cells representing putative CSCs from human NSCLA cells contained elevated levels of Rac1-GTP, enhanced in vitro migration, invasion, increased in vivo tumor initiating and lung colonizing activities in xenografted mice. However, CSC activity was also detected within the non-SP population, suggesting the importance of therapeutic targeting of all cells within a tumor. Further, pharmacological or shRNA targeting of Rac1 inhibited the tumorigenic activities of both SP and non-SP NSCLA cells. These studies indicate that Rac1 represents a useful target in NSCLA, and its blockade may have therapeutic value in suppressing CSC proliferation and metastasis.
Highlights
Lung cancer remains the leading cause of cancer deaths worldwide
Rac1shRNA1 expression partially reduced the proliferation of the lung cancer cells while Rac1shRNA2 more potently inhibited cell growth (Fig. 1B) and caused a significant decrease of number of colonies grown in soft agar colony formation assay (Fig. 1C)
These results indicate that Rac1 is required for the proliferative potential of non-small cell lung adenocarcinoma (NSCLA) cells
Summary
Lung cancer remains the leading cause of cancer deaths worldwide. The disease is broadly classified into two histopathological groups - small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC), with the later group representing ,80% of lung cancer cases. Often, existing chemotherapy, radiation therapy or surgery can only partly remove the tumor burden, leaving behind therapy resistant cancer cells that may regenerate the tumor at the primary site and/or metastasize to secondary sites to initiate new tumors. Recent publications have reported the identification of cancer initiating or cancer stem cells (CSCs) from blood [2], brain [3], breast [4], colon [5,6], hepatic [7], pancreatic [8], prostrate [9,10], as well as lung cancers [11,12,13]. The CSCs are identified either by unique cell properties such as Hoechst dye exclusion (Hoechst dye-low side population) or by expression of specific surface markers such as CD133, ALDH, or CD24/CD44, and they are frequently associated with chemotherapy and radiation therapy resistance. CSCs are defined by their stem cell like self-renewal capabilities, their ability to differentiate into cell types that constitute the bulk of the tumor, and to initiate tumors at a significantly reduced dosage in mouse xenograft studies [7,14]
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