Abstract
Due to their self-renewal and tumorigenic properties, tumor-initiating cells (TICs) have been hypothesized to be important targets for colorectal cancer (CRC). However the study of TICs is hampered by the fact that the identification and culturing of TICs is still a subject of extensive debate. Floating three-dimensional spheroid cultures (SC) that grow in serum-free medium supplemented with growth factors are supposed to be enriched in TICs. We generated SC from fresh clinical tumor specimens and compared them to SC isolated from CRC cell-lines as well as to adherent differentiated counterparts. Patient-derived SC display self-renewal capacity and can induce serial transplantable tumors in immuno-deficient mice, which phenotypically resemble the tumor of origin. In addition, the original tumor tissue and established SC retain several similar CRC-relevant mutations. Primary SC express key stemness proteins such as SOX2, OCT4, NANOG and LGR5 and importantly show increased chemoresistance ability compared to their adherent differentiated counterparts and to cell line-derived SC. Strikingly, cells derived from spheroid or adherent differentiating culture conditions displayed similar self-renewal capacity and equally formed tumors in immune-deficient mice, suggesting that self-renewal and tumor-initiation capacity of TICs is not restricted to phenotypically immature spheroid cells, which we describe to be highly plastic and able to reacquire stem-cell traits even after long differentiation processes. Finally, we identified two genes among a sphere gene expression signature that predict disease relapse in CRC patients. Here we propose that SC derived from fresh patient tumor tissue present interesting phenotypic features that may have clinical relevance for chemoresistance and disease relapse and therefore represent a valuable tool to test for new CRC-therapies that overcome drug resistance.
Highlights
Colorectal carcinoma (CRC) is the third most frequently diagnosed cancer type for both men and women and the second most common cause of cancer mortality in Western countries [1]
We found that patient biopsies are highly heterogeneous in terms of phenotypic markers (S1 Fig), questioning their reliability for the identification of tumor-initiating cell (TIC)
The sphere forming cell (SFC) frequency was similar among the CD133 low, medium and high population (S1 Fig), suggesting that CD133 expression does not correlate to enhanced sphere-forming capacity
Summary
Colorectal carcinoma (CRC) is the third most frequently diagnosed cancer type for both men and women and the second most common cause of cancer mortality in Western countries [1]. The two dominant concepts of carcinogenesis postulate stochastic (clonal evolution model) and hierarchic (cancer stem cell model) organization of tumors. According to the latter, subsets of cells, the so-called tumor-initiating cells (TICs) known as cancer stem cells (CSCs) are responsible for tumor evolution [2]. TICs are defined by their (1) selfrenewal, (2) differentiating and (3) tumor-initiating capacity. They have been described to propagate tumors that are capable of recapitulating the heterogeneity of primary tumors [3]. The remaining subset of TICs might induce the formation of new tumors, thereby leading to a rapid relapse of the malignancy [15]. Various recent studies support the clinical relevance of targeting TIC-associated genes [16]
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