A human colon cancer cell capable of initiating tumour growth in immunodeficient mice

Abstract

Colon cancer is one of the best-understood neoplasms from a genetic perspective, yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies. What has yet to be established is whether every colon cancer cell possesses the potential to initiate and sustain tumour growth, or whether the tumour is hierarchically organized so that only a subset of cells--cancer stem cells--possess such potential. Here we use renal capsule transplantation in immunodeficient NOD/SCID mice to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133+; the CD133- cells that comprised the majority of the tumour were unable to initiate tumour growth. We calculated by limiting dilution analysis that there was one CC-IC in 5.7 x 10(4) unfractionated tumour cells, whereas there was one CC-IC in 262 CD133+ cells, representing >200-fold enrichment. CC-ICs within the CD133+ population were able to maintain themselves as well as differentiate and re-establish tumour heterogeneity upon serial transplantation. The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem cells.

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…The first to identify such cells was Al-Hajj who found that breast cancer cells with CD24-CD44+ phenotype are able to form tumors that recapitulate their parental tumor when implanted in the mammary fat pad [26]. Immediately following this discovery, CD133+ cells were identified as tumor stem cells in glioblastoma brain tumors [27] and thereafter in colon cancer [28]. In the past few years, high ALDH1 activity levels have been used to identify CSCs in a variety of tumors including liver, head and neck, colorectal, breast, multiple myeloma, acute myeloid leukemia, and brain cancers [29][30][31][32][33][34][35].…”

“…Moreover, a link between poor prognosis and increased ALDH1 activity was found in breast tumors [33]. Since the above discoveries, as well as additional CSCs markers, CSCs have been prospectively isolated from a variety of malignancies, thus far including pancreas, skin, head and neck, and prostate cancers, and the list is ever growing [26][27][28][36][37][38]. The identification of CSCs was facilitated by significant progress achieved over the last several years in this field.…”

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

“…To date, the existence of CSCs has been proven in the context of many cancers, including those of leukemia, breast cancer, glioblastoma, prostate cancer, pancreatic cancer and colon cancer (Lapidot et al, 1994;Bonnet and Dick, 1997;Al-Hajj et al, 2003;Hemmati et al, 2003;Singh et al, 2003Singh et al, , 2004Collins et al, 2005;Ponti et al, 2005;Haraguchi et al, 2006;Patrawala et al, 2006;Li et al, 2007;O'Brien et al, 2007;Ricci-Vitiani et al, 2007). Recently, we have determined that HCC is hierarchically organized and originates from a primitive stem/progenitor group of cells for which CD133 þ precursors constitute one of the most immature stage (Ma et al, 2007).…”

“…To date, CD133 has also been shown to mark the CSC population in cancers of the brain, prostate, pancreas and colon (Hemmati et al, 2003;Singh et al, 2003;Li et al, 2007;O'Brien et al, 2007;Ricci-Vitiani et al, 2007). Preliminary studies have attributed the high expression levels of specific ABC drug transporters to the increased resistance of CD133 CSCs to chemotherapeutic agents (Dean et al, 2005;Haraguchi et al, 2006).…”

Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

“…Until now, CSCs have been reported in several types of solid tumors, including colorectal, breast, pancreatic, lung, and hepatocellular 49, 50, 51, 52. More and more in vivo evidence demonstrated that CSCs could promote MDR.…”