Direct reprogramming of stem cell properties in colon cancer cells by CD44

Abstract

Cancer progression is commonly segregated into processes of primary tumour growth and secondary metastasis. Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumour growth in cancer. However, the role of CSCs in cancer metastasis is unclear. In this study, we found that the C terminus of CD44 contributes to sphere formation and survival in vitro via the CD44-SRC-integrin axis. In addition, nuclear CD44/acetylated-STAT3 is required for clonal formation in vitro and tumourigenicity in vivo. Nuclear CD44 binds to various promoters identified by chromatin immunoprecipitation-seq, including that of c-myc and Twist1, leading to cell fate change through transcriptional reprogramming. We propose that nuclear CD44/acetylated-STAT3 performs an unexpected tumour-progressing function by enhancing cell outgrowth into structures where cells with properties of CSCs can be generated from differentiated somatic cells in suspension culture, and then exhibit attributes of cells that have undergone an epithelial-mesenchymal transition, leading to tumour metastasis, and a resulting worse prognosis.

Understanding cancer stem cell heterogeneity and plasticity

“…In fact, simply overexpressing certain oncogenic molecules (e.g., Nanog, CD44, Twist, hTERT, etc) is sufficient to reprogram primary non-tumorigenic cells or bulk cancer cells into stem-like cancer cells [136][137][138][139][140][141]. These latter observations [136][137][138][139][140][141] are consistent with the observations that such 'stemness' molecules are most frequently expressed in undifferentiated tumor cells. Finally, as CSCs constantly interact with their microenvironment, protumorigenic alterations in the microenvironment (e.g., in stromal cells) will likely affect CSC properties and promote plasticity in CSC progeny [142,143].…”

“…Experimental EMT and inflammatory cytokines IL-6, IL-8, TGFβ, and TNFα can all promote the manifestation of CSC phenotypes and properties [130][131][132][133][134][135]. In fact, simply overexpressing certain oncogenic molecules (e.g., Nanog, CD44, Twist, hTERT, etc) is sufficient to reprogram primary non-tumorigenic cells or bulk cancer cells into stem-like cancer cells [136][137][138][139][140][141]. These latter observations [136][137][138][139][140][141] are consistent with the observations that such 'stemness' molecules are most frequently expressed in undifferentiated tumor cells.…”

Unbiased Proteomic and Transcript Analyses Reveal that Stathmin-1 Silencing Inhibits Colorectal Cancer Metastasis and Sensitizes to 5-Fluorouracil Treatment

“…These include SNAI2, SNAI3, TCF4, ZEB1, and ZEB2, which have direct affinity for the CDH1 promoter, as well as TWIST1, FOXC2, and GSC, which regulate CDH1 expression indirectly (12). Strong inhibition on CD44 expression also supports the loss of matrix invasion (13) after STMN1 silencing, and likely prevents the direct reprogramming of colorectal cancer cells (14). These transcript changes following stable STMN1 silencing strongly indicate a reversal of EMT phenotype, especially in the metastatic E1 cell line.…”

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

“…Previous work by Tammi et al (31) indicated that the association of HA with CD44 causes internalization of CD44 fragments, and some translocate to the nucleus (32) and modulate gene transcription by direct association and activation of gene promoters (33). To investigate whether such a mechanism operated in our cocultures, we probed for the localization of CD44 in MDA-MB-231 and MDA-MB-231 MSC .…”