Origin of Cancer Stem Cells: The Role of Self-Renewal

and Differentiation

A paper by ,
Xiong-Zhi Wu
 Introduction

Cancer stem cells may be caused by transforming mutations occurring in stem cells,
progenitor cells, mature cells, and cancer cells. The genetic program controlling self-
renewal and differentiation is a key issue in origin of cancer stem cells.

Self-renewal and differentiation potential are features of stem cells.

Self-renewal allows stem cells to persist during the lifetime of the organism, and
differentiation potential allows stem cells to provide the progenitors and mature cells
for tissue genesis, maintenance, and regeneration after stress or injury.
 Differentiation is usually considered to be a one-way process of specialization as cells develop
the functions of their ultimate fate and lose their immature characteristics, such as self-
renewal.

 Progenitor cells, the products of stem cells losing the activity of self-renewal, could
differentiate to mature cells, which have the feature of differentiation and lose the activity of
self-renewal

 The roles for cancer stem cells have been demonstrated for some cancers, such as cancers of
the hematopoietic system, breast, brain, prostate, pancreas, and liver.

 Cancer stem cells could self-renew and produce cancer cells instead of normal cells. These
properties are exactly what cancer stem cells exhibit in initiating and maintaining malignant
growth. However, the origin of cancer stem cells remains elusive.

 This article focuses on current scientific controversies related to the establishment of the
cancer stem cells—in particular, how self-renewal and differentiation block might contribute
to the evolution of cancer.
 Pathways in Self-Renewal,
Differentiation, and Carcinogenesis

 Many pathways that are classically associated with cancer may also regulate stem
cell self-renewal and differentiation.

 Role of Wnt, Hedgehog, Shh, and Notch signalling pathways in regulating stem cell
self-renewal have shed new light on carcinogenesis

 Similar signalling pathways may regulate self-renewal in normal and transformed

stem cells.

 For instance, the Wnt signalling pathway is activated by the binding of Wnt to their
receptors, leading to the release of β-catenin from the degradation complex and
facilitating its entry into the nucleus, where it regulates target gene transcription
that modifies stem cell self-renewal or differentiation, such as cyclin D1 and C-myc
Wnt Signalling pathway
 Although similar signalling pathways may regulate self-renewal in normal stem cells
and cancer stem cells, there are mechanistic differences in some cancers. Deleting
the Pten tumour suppressor gene in leukaemia-initiating cells leads to
myeloproliferative disease.

 Pten deletion also promotes hematopoietic stem cell proliferation. However, it leads
to hematopoietic stem cell depletion by inhibiting self-renewal.

 These effects are mostly mediated by mTOR as they are inhibited by rapamycin.
Rapamycin not only depletes leukaemia-initiating cells but also restores normal
hematopoietic stem cell function.

 Interestingly, the mechanistic differences of self-renewal between normal stem cells

and cancer stem cells can thus be targeted to deplete cancer stem cells without
damaging normal stem cells.
 TISSUE -SPECIFIC STEM CELLCELLS AND
CANCER STEM CELLS

Cancers are caused by transforming mutations occurring in tissue-specific stem cells.

As bipotential liver stem cells, oval cells have the bipotential for differentiating into hepatocyte
and bile cells. oval cells are behind some hepatocellular carcinomas.

As bipotential liver stem cells, oval cells have the bipotential for differentiating into hepatocyte
and bile cells. Much research supports the notion that oval cells are the troublemakers behind
some hepatocellular carcinomas.
 PROGENITOR CELLCELLS AND CANCER
STEM CELLS

The origin of human tumours has been recently debated as originating from stem or progenitor
cells. Progenitor cells, which lose the activity of self renewal, are the link between tissue-specific
stem cells and mature cells.

If cancer stem cells originate from progenitor cells, the transform cells must gain the self-
renewal activity. There are two major nonexclusive hypotheses about the transformation:

 the cells may dedifferentiate to tissue-specific stem cells

 they may obtain the self-renewal activity by activating the self-renewal-associated genes.

MOZ-TIF2–transduced progenitors have been serially replated in methylcellulose cultures and

continuously propagated in liquid culture, which resulted in an acute myeloid leukemia in vivo
that could be serially transplanted
Leukemia stem cells are defined as transformed hematopoietic stem cells or committed
progenitor cells that have amplified or acquired the stem cell capacity for self-renewal.34
Leukemia stem cells possess an immunophenotype and global gene expression profile similar to
that of normal granulocyte macrophage progenitor cells
Transformed myeloid progenitors aberrantly express a small number of stem cell genes, while
still displaying the overall gene expression profile of myeloid progenitor cells. The transformed
progenitors do not become stem cells but rather acquire stem cell–like behavior.

Leukemia stem cells can thus be generated from committed progenitors without widespread
reprogramming of gene expression, and a leukemia self-renewal–associated signature is
activated in the process.
 BONE MESENCHYMAL STEM CELLS AND
CANCER STEM CELLS

In kidney allograft recipients, bone marrow–derived stem cells originating from a grafted kidney
may migrate to the skin and undergo transformation into cancer

Adult MSCs may be targets for malignant transformation and undergo spontaneous
transformation after long-term

in vitro culture, supporting the hypothesis that some cancer stem cell originate from
multipotential stem cell. Transformed BMSCs could form many tumor types, including epithelial
tumors, neural tumors, muscular tumors, tumors of fibroblasts, blood vessel endothelial tumors,
and teratoma
If cancer stem cells could originate from the multipotential stem cells, the transform cells must
gain the differentiation feature of the special tissue. There are two major nonexclusive
hypotheses about how transformed cells retain features of the special tissue:

 differentiation,
 fusing to tissue-specific stem cell/progenitor/mature cells
 MATURE CELLS AND CANCER STEM CELLS

Mature cells are the final differentiation cells that lose the activity of self-renewal in most
conditions.

Two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises
from stem cells as a result of maturation arrest, or from dedifferentiation
of mature cells

Taranger et al reported on the induction of dedifferentiation associated with genome-wide

programming of gene expression in epithelial 293T cells treated with an extract of
undifferentiated human NCCIT carcinoma cells.

The transition from 293T to pluripotent cell phenotype involves a dynamic upregulation of genes
encompass embryonic and stem cell markers, including OCT4-, SOX2-, NANOG-, and Oct4-
responsive genes, concomitant with down regulation of 293T genes and differentiation
indicators, such as A type lamins.
 Conclusion

Self-renewal and differentiation potential are features of stem cells. Cancer stem cells could
selfrenew and produce cancer cells instead of normal cells.

However, the origin of the cancer stem cell remains elusive. The hypothesis is that cancer stem
cells are caused by transforming mutations occurring in multipotential stem cells, such as MSCs,
tissue-specific stem cells, progenitor cells, mature cells, and cancer cells.

Progenitor cells obtain the self-renewal activity by activating the self-renewal–associated genes
rather than dedifferentiating to tissue-specific stem cells.

Most cancer retains the feature of the primary tissue. If cancer stem cells originate from the
multipotential stem cells, the transform cells must gain the differentiation feature of the special
tissue.
Mature cells and cancer cells dedifferentiate into cancer stem cells by genetic and/or epigenetic
events to gain self-renewal activity and lose some features of differentiation.

Cellular differentiation is usually considered to be a one-way process of specialization as the cells

develop the functions of their ultimate fate and lose such immature characteristics as self-
renewal.

The challenge is understanding the genetic programs controlling the stem cell state—that is, self-
renewal and differentiation. Cracking the molecular codes that govern the stem cell state turns
out to be a difficult task, partly because a single gene may exhibit distinct activities when
expressed in different cell types.

Comprehending the cell-context–dependent readout of any given gene requires an integrated

knowledge of the complex cellular machinery, a platform that can be provided by the research
on cancer stem cells