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Medical Hypotheses (2001) 57(5), 655±666
&2001 Harcourt Publishers Ltd
doi: 10.1054/mehy.2001.1435, available online at http://www.idealibrary.com on
1
Transdifferentiation of
neoplastic cells
Z. Zhang,
1
X.-M. Yuan,
2
L.-H. Li,
1
F.-P. Xie
1
1
Department of Pathology, Dalian Medical University, Dalian, China;
2
Division of Pathology II, Linko
Èping University, Linko
Èping, Sweden
Summary Transdifferentiation is a process in which a stable cell's phenotype changes to that of a distinctly different
cell type. It occurs during certain physiological processes and leads to transition of tumor cell phenotypes. The latter
process includes neoplastic epithelial±epithelial transition, neoplastic epithelial±mesenchymal transition, neoplastic
mesenchymal±epithelial transition and transition between non-neural and neural neoplastic cell. This phonomenon is
exemplified in some origin-debated tumors, such as carcinosarcoma, pleomorphic adenoma, synovial sarcoma, Ewing's/
pPNET, and malignant fibrohistiocytoma. We propose that differentiation disturbance of cancer cells should include not
only undifferentiation and dedifferentiation, but also transdifferentiation as well. Tumor cell transdifferentiation may be
influenced or determined by cellular genetic instabilities, proliferation and apoptosis, as well as by extracellular matrix and
growth factors. &2001 Harcourt Publishers Ltd
INTRODUCTION
Transdifferentiation is a process in which a stable cell's
phenotype changes to that of a distinctly different cell
type. Transdifferentiation may be a kind of differentiation
disturbance occurring in neoplasia, causing the tumor
cells to express a phenotype different from that of their
progenitor (1).
NEOPLASTIC EPITHELIAL±EPITHELIAL
TRANSITION
Normal epithelial transdifferentiation
Transition between different types of epithelium may be
a normal phenomenon in the adult body. For example,
squamous epithelium lining the mouse vagina changes
cyclically in response to sex hormones secreted during the
normal estrous cycle (2).
Epithelial metaplasia
In pathological conditions, mature epithelial cells of one
phenotype change into another, a process called epithelial
metaplasia. Since the resulting cancer cells are immature,
`metaplasia' seems to be a less than accurate term to
describe the transdifferentiation of neoplasia, although
metaplasia is essentially a transdifferentiation process
occurring in non-neoplastic lesions.
Transition of carcinoma cell types
Conversion of carcinoma cell type, resulting in hetero-
genicity of the tumor, is not uncommon. In some cases,
dual-differentiation was found even in individual cells.
The amphicrine carcinomatous cell may exhibit neuro-
endocrine features at its base, and mucus production
and secretory activity in the apical portion (3). Glandular,
squamous, and neuroendocrinal phenotypic features
have been found in the same carcinomatous cell (4).
Chemically induced proliferation of Clara cells in bron-
chioli of the hamster or mouse may initially form
tumors composed of Clara cells, which subsequently
are converted into adeno- or squamous carcinoma
(5,6). Experimental proliferation of hamster bronchial
655
Received 12 January 2001
Accepted 25 May 2001
Corr esponden ce to:P rofessor Zhong Zhang, Pathological Center,
Dalian Medical University, 465 Zhongshan Road, Dalian 116027, P R China.
Fax: 86 0411 472 0610
endothelium and adult bovine or rodent thyroid
follicles can be induced to form mesenchyme when sus-
pended in 3D collagen gels (25). In this process, epithelial
phenotypes such as cytokeratin, cell junction and apical-
based polarity, are lost in the elongated and vimentin-
positive cells, i.e. fibroblasts, which emigrate from the
former surface of the explant. When the cultured cell line
(NBT-II) of a rat bladder carcinoma was attached to the
collagen type I in the medium, or a substitute for serum,
ultroser G, was added to the medium, epithelial-type
cancer cells were converted into the fibroblast type. If the
inducing factors are removed, the epithelial phenotype
may be restored (26).
The effects of differentiation, dedifferentiation and
redifferentiation require a coordinated network that simu-
ltaneously controls cell growth and differentiation. Dif-
ferentiation-induced cells progress through the G
0
-arrest
cycle, whereby a certain population of cells retains the
capacity to de- and redifferentiate and re-enter the cell
cycle. In contrast, the rest of the differentiated population
enters the irreversible G
0
phase (terminal commitment)
that finally results in programmed cell death (27).
Receptor-mediated actions and via intracellular second
messengers cause growth factors to stimulate the cells in
the quiescent G
0
phase of the cell cycle. When the tran-
scription factors are activated, DNA synthesis is initiated
and followed by cell division and dedifferentiation, or
further redifferentiation.
On the other hand, expression of growth factor recep-
tor may influence the regulation of E-cadherin-mediated
cell adhesion. There is increasing experimental evidence
to suggest that the epidermal growth factor receptor of
tyrosine phosphorylation may lead to inactivation of the
E-cadherin±catenin complex in cancer cells, through its
interaction with beta- or gama-catenin in the cytoskeleton
(28). Hepatocyte growth factor-scatter factor (HGF-SF)
has been shown to produce effects similar to those of
epidermal growth factor (EGF) with phosphorylation of
catenins (29). E-cadherin plays a critical role in the
establishment and maintenance of epithelial morphology
and differentiation, and loss of E-cadherin may result in
epithelial±mesenchymal transition.
Cultured neonatel rat hepatocytes (30), mouse mam-
mary gland epithelial cells (NMuMG) (31), nasophanryn-
geal carcinoma cells (CG-I) (32), and rat bladder carcinoma
NBT-II cells (33) undergo epithelial±mesenchymal transi-
tion when the medium contains growth factor, such as
EGF, TGF-alpha, -beta, and some subtypes of fibroblast
growth factor (FGF). Within a few hours of the addition of
nanogram quantities of these factors, the peripheral cells
of NBT-II epithelial islands start to detach and migrate.
Within 10±15 hours, all cells convert into fibroblast-like
cells. This change is reversible by withdrawal of the growth
factor. Although growth factors and their receptors
principally promote cell proliferation and dedifferentia-
tion, some growth factors may also negatively regulate
tumor progression (18).
Transition of carcinoma to carcinosarcoma
Several hypotheses have been proposed to explain the
origin of biphasic appearance of carcinosarcoma. Recent
findings from comparative molecular analysis of the neo-
plastic epithelial and mesenchymal components lend
strong support to the monoclonal multidirectional histo-
genesis of these tumors. Using chromosomal inactivation
assays, k-ras mutation analysis, p53 mutation analysis
and loss of heterozygosity (LOH) studies (34±38), it has
been shown that carcinomatous and sarcomatous
elements in carcinosarcomas share common genetic
alterations, strongly supporting to the monoclonal multi-
directional histogenesis of these tumors. It is generally
thought that there is a single totipotential stem cell, which
gives rise to the multiphasic appearance of carcino-
sarcoma. However, it is highly doubtful whether a specific
totipotential stem cell exists between adult epithelial cells.
Usually both carcinosarcomas and carcinomas occur at
similar sites. If carcinosarcoma originates from totipoten-
tial stem cells, the latter should coexist with the tissue±
determined specific stem cell which gives rise to carci-
noma. Since it is likely that both types of stem cells at the
same location are exposed to the same carcinogen, why is
there such disparity in incidence between carcinoma and
carcinosarcoma?
We know that the primitive mesenchyme derives from
proto-epithelium in the embryo, and that normal and
neoplastic epithelial cells may convert into mesenchyme.
In fact, clinically, carcinoma may progress into carcino-
sarcoma. Some examples of pure endometrial carcinoma-
carcinosarcomatous metastases conversion have been
documented (39). It also has been reported that carcino-
sarcoma may arise in duct papilloma of breast or sweat
gland adenoma (40,41). In two of 16 cases of gynecological
carcinosarcomas with homogeneous or loss of hetero-
geneous (LOH) patterns, Fojii et al. found the specific pat-
terns of genetic progression to be consistent with
sarcomatous components of the neoplasms arising from
carcinomatous components (38). The evidence includes
additional LOH consistent with genetic progression
and diversion from original carcinoma to carcinoma/
sarcoma foci, and additional LOH consistent with genetic
progression from original carcinoma to carcinosarcoma
only in metastatic foci (38). When the cultured rat
hepatocytes were transformed by methyl-nitroso-nitroso-
guanidine and then transplanted into homogenous
rats, they grew into the following tumor types: epidermoid
carcinoma, glandular carcinoma, hepatocarcinoma, undif-
ferentiated carcinoma, sarcoma and carcinosarcoma (42).
Transdifferentiation of neoplastic cells 657
&
2001 Harcourt Publishers Ltd Medical Hypotheses (2001) 57(5), 655±666
NEOPLASTIC MESENCHYMAL±EPITHELIAL
TRANSITION
Mesenchymal±epithelial transition in the embryo
During organogenesis, certain primitive mesenchyme
may regain epithelial phenotype. Metanephric blastema
is composed of highly proliferative mesenchyme.
When the primitive epithelial ureteric bud grows into the
blastema, a reciprocal inductive interaction occurs bet-
ween mesenchyme and epithelium, and the primitive
renal vesicle (epithelial structure) is formed from the
mesenchyme. The formation of renal vesicle reflects
de-repression of epithelial promoters, resulting from
inhibition of the expression or transcriptional activities of
mesenchymal transcription factors.
As mesenchyme undergoes transition to epithelium,
the intermediate filament is changed from vimentin to
cytokeratin, and the non-polarized, loosely associated cells
compact together to form polarized, closely associated
cells. The compaction of cells is mediated by E-cadherin
in a process that is mechanistically analogous to integrin-
mediated spreading of fibroblasts on an extracellular
matrix. E-cadherin expression is crucial for mesenchymal±
epithelial transition. The mechanism controlling
E-cadherin activation probably involves alteration of the
catenin cytoplasmic plaque protein, in the actin cytoske-
leton, or the interactions between them (43,44). If, as
Birchmeir and Behrens (45) pointed out, the endogenous
E-cadherin promoter region is inaccessible in nonepi-
thelial cells, suggesting that the transcriptionally inactiva-
ted gene is packaged into chromatin or is otherwise
modified, e.g. by methylation, then regulation of epithe-
lial-specific expression of E-cadherin largely is due to
specific suppression of promoter activity in nonepithelial
cells, rather than specific activation in epithelial cells.
Expression of epithelial marker in normal and
neoplastic mesenchyme
Decidual stromal cells may express CK8, 18 and 19 when
cultured in either Condimed or Chang conditioned
medium. Similar cytokeratin positivity could also be seen
in cultured fetal fibroblasts from skin, chorionic villi and
lung, but not in young or adult skin fibroblast cultures
using the same cultured conditions (46).
Neoplastic cells co-expressing Vim and CK (and/or
EMA), or expressing E-cadherin, or with epithelial-like
morphology may be found in some primary mesenchymal
tumors.
Scattered cells which were immunocytochemically
positive to CK8 and 18 were found in cultures of Vim-
positive, transformed mesenchymal cell lines, including
SV40-transformed human fibroblasts, rhabdomyosar
coma, rat smooth muscle-derived cells, murine sarcoma
and hamster BHK-2 cells. When cultures of human SV80
fibroblasts were treated with 5-aza-cytidine, the fre-
quency of CK-positive cells increased significantly, but no
cells became positive upon addition of desmosomal
proteins (47).
Using the monoclonal antibody HECD-1, the extra-
cellular domain of E-cadherin immunoreactivity was
identified in a few soft-tissue tumors, especially those with
epithelioid features, including pleomorphic rhabdomyo-
sarcomas, clear cell sarcomas, epithelioid sarcomas,
synovial sarcomas and diffuse mesotheliomas (48).
Treatment with 5-aza-cytidine induces the formation
of a low proportion of CK8-containing intermediate fila-
ments in murine fibroblastoidal or myoblastoidal cells
derived from teratocarcinoma cells, with co-expression of
CK18 and/or 19 in some of those cells. Rare stable cell
lines of these cells display true epithelial morphology with
typical desmosomes and CKs other than 8 and 18 (49).
Effects of tumor suppressor gene and oncogene
The Ela gene of adenovirus may act as a tumor suppressor
gene in certain human tumor cell lines, not by killing
tumor cells, but by converting them into a non-trans-
formed phenotype. Frisch demonstrated that Ela expres-
sion partially convert several human tumor cells
(rhabdomyosarcoma, fibrosarcoma, osteosarcoma) and
fibroblasts into an epithelial phenotype (17).
Co-expression of the human Met receptor (met is an
oncogene) and its ligand, HGF/SF, in NIH3T3 fibroblasts
cause the cells to become tumorigenic in nude mice.
Tsarfary et al. reported that the resultant tumors display
lumen-like morphology, contain carcinoma-like focal areas
with intercellular junctions resembling desmosomes, and
co-express CK and Vim (50).
Whether the oncogene and tumor suppression gene
take part in the mesenchymal±epithelial transition merits
further exploration.
HISTOGENESIS OF SOME
BI-DIFFERENTIATION TUMORS
Pleomorphic adenoma
Currently it is believed that the pleomorphic adenomas
of the salivary gland originate from intercalated duct
epithelium, while myxomatous and chondroid substances
are produced from myoepithelium. Recently, Aigner et al.
(43) found there were some areas with unequivocal epi-
thelial and mesenchymal differentiation in this tumor
tissue. Many areas displayed transitional phenotype cells
and the neoplastic epithelial cells may transdifferentiate
into mesenchymal cells.
658 Zhang et al.
Medical Hypotheses (2001) 57(5), 655±666
&
2001 Harcourt Publishers Ltd
Synovial sarcoma±real carcinosarcoma
Synovial sarcoma rarely originates from the synovial
membrane lining joints and tendon sheaths. The synovial
intima is composed of macrophage-like cells and fibro-
blast-like cells. The flattened, cuboidal or columnar lining
cells of spaces in synovial sarcoma tissue show epithelial
differentiation to an adenomatous, or, in rare instances,
focal squamous, but not synovial intima type. Thus,
synovial sarcoma should be identified as a type of carcino-
sarcoma or carcinoma of mesenchymal tissue (51).
Spindle cell type monophasic, biphasic, and glandular type
monophasic synovial sarcoma may be regarded respec-
tively as sarcoma, carcinosarcoma and carcinoma in the
differentiation spectrum of this neoplasm.
Epithelioid sarcoma
In view of the immunohistochemical evidence, epithelioid
sarcoma may be hypothesized to be a type of mesenchy-
mal carcinoma with simple epithelial differentiation.
Electron microscopic photos of the tumor showed a
spectrum of cellular differentiation from fibrohistiocytic
cells to epithelial-type cells with junctions, microvilli and
tonofilaments. Spindle cells showed myofibroblastic and
fibroblastic differentiation (52). All the tumors display
both vimentin and epithelial markers, just like some
poorly differentiated carcinoma cells. In some cases the
tumor cells may co-express neurofilament protein,
neuron-specific enolase (NSE), or even synaptophysin (53).
Karyotypes of the RM-HS1 cell line were reported to
contain extensive numerical and structural rearrange-
ments, with up to 24 marker chromosomes (54). Quezado
reported allellic loss on chromosome 22q in six of 10
epithelioid sarcomas (55).
Malignant mesothelioma
The regenerating mesothelium may originate from
either the surrounding uninjured mesothelial cell popu-
lation or from subserosal cells. It has been suggested
that subserosal cells are distinct from other connective
tissue cells in this ability to co-express Vim and CK, and
serve as replicated cells which can differentiate into
surface epithelium. To study this phenomenon, both the
visceral and parietal peritonea of rats was incised and
allowed to heal with resultant proliferation and differ-
entiation of subserosal cells. The proliferated subserosal
cells change morphologically from the original spindle-
shaped, fibroblast-like cells to polygonal surface epithelial
cells (56). Following injection of crocidolite asbestos
into the peritoneal cavity of rats and mice, the subserosal
cells proliferated to form a tumorous nodule, in which
the spindle cells differentiated into surface mesothelial
cells. No evidence of proliferation by the original surface
mesothelial cells in response to the asbestos was found
(56). Most malignant mesotheliomas are characterized
by multiple, complex and heterogeneous chromosomal
aberrations. Sreekantaiah et al. reported that the 3p
abnormalities, perhaps causally related to the develop-
ment of this malignancy, and del(6q) might represent
a primary change (57). Malignant mesothelioma originate
from subserosal mesenchymal cells. As its normal pro-
genitor possesses bidifferentiated potential, this tumor
may show a differentiation spectrum from sarcoma to
carcinosarcoma and carcinoma.
Adamantinoma of long bone
Adamantinoma of long bone, composed of epithelial and
fibrous components, is closely related to osteofibrous
dysplasia (OFD). Most OFDs contain isolated or aggregated
keratin-positive cells, which are identical to OFD-like
adamantinoma. The recurrent focus of OFD-like tumor
with isolated keratin-positive cells may be a classic ada-
mantinoma with abundant epithelium (58). Hazelbag
et al. found: (a) focal basement membrane substances in
OFD-like areas with keratin-positive cells; (b) increased
basement membrane continuity with gain of histological
distinction between epithelial and fibrous components;
and (c) strong tenascin reactivity directly surrounding
well-developed epithelial fields, with weaker staining
more distantly (59). Hazelbag et al. suggested that the
epithelial component in adamantinoma may be trans-
formed directly from osteofibrous tissue (59).
HISTOGENESIS OF EWING'S/pPNET
Hypothesis on the origin of Ewing's sarcoma
Ewing's/pPNET (Ewing's sarcoma/peripheral primitive
neuroectodermal tumor) is a family of bone and soft-
tissue tumors, in which the typical Ewing's sarcoma, with
a mesenchymal phenotype, lies at one end of the differ-
entiation spectrum and pPNET, with clear evidence of
a neural marker, lies at the other end. Some authors had
suggested that Ewing's sarcoma originates from the
mesenchymal or primitive form of connective tissue (60).
Aurias et al. and Wang-Peng et al. found a coincidental
cytogenetic abnormality in ES and pPNET (60). In 1990
several groups of investigators found that, through the
addition of agents such as retinoic acid to the cultures, the
ES cells may be induced in vitro to express neural markers
(60). Currently, many pathologists prefer to support the
view that Ewing's/pPNET originates from neural crest
cells. The embryonic neural crest has the potential to
differentiate into mesenchyme, which could explain the
expression of Ewings' mesenchymal phenotype.
Transdifferentiation of neoplastic cells 659
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2001 Harcourt Publishers Ltd Medical Hypotheses (2001) 57(5), 655±666
Against the hypothesis of a neural origin of
Ewing's/pPNET
Although normal mesenchyme does not express neural
differentiation, `neural' markers may be found in mesen-
chymal tumors. For example, epithelioid sarcoma cells
express neurofilament, NSE and synaptophysin protein
(61); MFHs have neurofilaments and are neural-associated
antigen-positive (62); synovial sarcoma may be immuno-
histochemically positive to neurofilament 68kd, S-100,
Leu-7 and GFAP (63).
Molenaar and Muntinghe (64) studied the expression of
neural cell adhesion molecules and neurofilament protein
isoforms in bone and soft-tissue sarcomas. They found
that both neural markers are expressed in rhabdomyo-
sarcoma, leiomyosarcoma, fibrosarcoma, MFH, malignant
rhabdoid tumor and fibromatosis, and are N-CAM-
positive in synovial sarcoma. Desmoplastic small round
cell tumors (DSRCT) may show positive staining with
antibodies to NES, Leu-7 and other neural antigens,
although they are more likely from mesenchymal tissue
such as subserosal cells (65). Thus, the expression of
`neural' markers does not prove a neural origin for the
tumor.
Neuroblastoma originates from the sympatho-adrenal
lineage of the neural crest. Its characteristic chromosome
changes are deletion of 1p36.2±3, amplification of the
proto-oncogene MYCN, and abnormalities of the chromo-
some number (66). The special cytogenetic aberration
found in Ewing's/pPNET is chromosomal translocation
resulting in gene fusion. One of the criteria used to diag-
nose classic neuroblastoma is the presence of Homes±
Wright pseudorosettes. However, the number of rosettes
seen by most investigators in pPNETs is few or none (60).
The differentiation-potential of neuroblastoma shows
neural mono-direction. Ewing's/pPNET shows multi-
differentiation and may overlap somewhat in appearance
with DSRCT, or even alveolar rhabdomyosarcoma, both
of which also show characteristic chromosome translo-
cation. From these points, Ewing's/pPNET is more closely
related to non-neural derived tumor in phenotype and
cytogenetic profile. The discovery of a hybrid tumor
comprised of Ewing's/pPNET and DSRCT further demon-
strated that DSRCT and pPNET may share a common
histogenesis (67).
Neural crest cells detach from the dorsal neural tube
and migrate, colonize and differentiate into a large
variety of derivatives. These include the neurons and glial
cells of the peripheral nervous system, endocrine cells,
melanocytes and the so-called mesoectoderm, which
plays a crucial role in formation of the connective tissues
and skeletal structures of the head. Most of the Ewing's/
pPNET were located outside the head, neck and regions
unrelated to any specific structures of the peripheral or
sympathetic nervous systems. These tumors are thought
to originate from abnormally migrated neural crest cells.
However, the occurrence of Ewing's/pPNET in adult and
aged patients suggests that an implanted neuroecto-
dermal fetal origin of these tumors is unlikely. Fukunaga
et al. reported a case of carcinosarcoma with neuroecto-
dermal differentiation which occurred in the uterus of
a 54-year-old woman (68). The neoplastic elements
included squamous carcinoma, leiomyosarcoma and
islands of small- to medium-sized cells with rosette-like
formation and immunoreactivity for GFAP, Leu-7, NSE
and synaptophysin. Certainly in this case, the cells with
neural differentiation did not arise from neural crest cell.
Relation between chromosome translocation and
morphogenesis in Ewing's/pPNET
Ewing's/pPNET is characterized by specific chromosomal
translocations, which result in a fusion gene and its
encoding chimeric protein. In at least 90% of Ewing's/
pPNET, the translocation is t(11;22) (q24;q12), resulting in
fusion of parts of the EWS gene with parts of the FLI-1 gene
encoding for transcription factor. In the encoded chimeric
protein, the amino-terminal EWS domain is linked to the
DNA-binding domain of the transcription factor. In
another 5% of cases, t(21;22) (q22;q12) translocation is
present, which involves the genes for EWS and ERG.
Another rare translocation is t(7;22) (p22;q12), which
results in EWS/ETV-1. FLI-1, ERG and ETV-1 all belong
to the ETS proto-oncogene family (69).
EWS/FLI-1 (or EWS/ERG, ETV-1) is a transcription
factor. May et al. demonstrated that EWS/FLI-1 efficiently
transformed NIH3T3 cells, but FLI-1 did not (70).
Experiments with EWS/FLI-1 deletion mutants indicated
that both EWS and FLI-1 domains are necessary for
transformation by the t(11;22) translocation product
(71). Recently, Teitell et al. reported that NIH3T3 fibro-
blasts infected with either EWS/FLI-1 or EWS/ETV-1
resembled small round cell tumor microscopically, and
showed both epithelial and neuroectodermal pheno-
types as represented by CK15 expression, dense junc-
tion, and neurosecretory granule formation (72). The
altered cells lost both extracellular collagen deposi-
tion and RER, indicating a loss of mesenchymal
differentiation.
Although all the Ewing's/pPNETs tumors harbor an
identical model of the chromosomal translocation, its
differentiated spectrum includes a mesenchymal pheno-
type at one end, and a neural at the other. Other small cell
tumors of soft tissue, such as DSRCT, polyphenotypic
tumors, and even a few cases of alveolar or embryonal
rhabdomyosarcoma, may also possess t(11;22) (q24;q12)
translocation and the EWS/FLI-1 fusion gene (73,74). From
these findings, we deduce that expression of the neural
660 Zhang et al.
Medical Hypotheses (2001) 57(5), 655±666
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2001 Harcourt Publishers Ltd
phenotype in Ewing's/pPNETs is not decided merely by
the formation of EWS/FLI-1 or EWS/ERG fusion gene, but
also requires the activation of certain genes related to
neural differentiation.
Difference in origin between cPNET and
Ewing's/pPNET
There are two categories of primitive neuroectodermal
tumors (PNETs): central (cPNET ) and peripheral (pPNET)
categories (75). A tumor which originates in the brain or
spinal cord, such as medulloblastoma, is classified as a
central PNET. Adrenal and extra-adrenal neuroblastomas
and Ewing's/pPNET (in soft tissue and bones) are exam-
ples of a peripheral PNET. Because they occur in these
specific locations, central PNETs and neuroblastomas may
derive from neural tissue. As for Ewing's/pPNET, we
hypothesize that they arise from mesenchymal tissue. In
view of the preceding part of this review, the reasons may
be summarized as follows: expression of neural markers
does not signify a neural origin; the primary location of
most tumors is unrelated to any specific structure of the
nervous system; its phenotype is distinct from that of
neuroblastoma but similar to that of some small cell tumors
of the mesenchyme; its characteristic chromosome trans-
location and fusion gene, with which the infected 3T3
fibroblasts gain neuroectodermal phenotypes and loss of
mesenchymal differentiation. It is evident that the func-
tion of EWS/FLI-1 or EWS/ERG and EWS/ETV-1 is not only
to initiate the transformation of mesenchymal cells, but
also to regulate the phenotypic expression of Ewing's/
pPNET.
Vasoactive intestinal peptide (VIP) is a neuromodulator
which regulates both proliferation and differentiation of
neuronal precursors. Fruhwald et al. analyzed cPNET cell
lines, cPNET tumors and Ewing's/pPNET, using reverse
transcriptase-polymerase chain reaction and Southern
hybridization (76). They found that VIP receptor 1 (VIPR1)
and VIPR2 are more highly expressed in both primary
cPNET tumors and cPNET cell lines. They pointed out
that this result may reflect the divergent pathways of
cPNET toward neural differentiation and Ewing's/pPNET
to mesenchymal cells. The question is how such divergent
pathways of differentiation occur. Another possible
explanation is that the origin of cPNET is distinct from
that of pPNET; the former from neural tissue, and the
latter from mesenchymal cells.
HISTOGENESIS OF MALIGNANT
FIBROHISTIOCYTOMA
Malignant fibrohistiocytoma (MFH) is composed
of fibroblast-like cells, histiocyte-like cells and an
intermediate cell type (77,78). These neoplastic cells may
show myofibroblast-like differentiation, occasionally
acquire certain properties of osteoblasts or chondroblasts,
and immunohistochemically express CK, epithelial
membrane antigen (EMA) neurofilaments (NF) and
neural-associated antigens (79±82).
Heterogeneity of MFH
Histocyte origin
Since the cases studied did not react with anti-monocyte-
macrophage antibodies, some investigators are moving
away from histiocyte-origin hypothesis (83±88). However,
other investigators have reported that MFH does express
antigenic markers specific for monocytes-macrophages
(89±91). Yumoto and Morimoto inoculated SV40-trans-
formed bone marrow macrophages in syngeneic mice to
produce a transplantable tumor (92). The tumor was
composed of spindle cells with histiocytic function such
as storiform arrangement. Some tumor cells present a
transitional form between histiocyte-like and fibroblast-
like cells. This experiment demonstrated that MFH may be
derived through transdifferentiation of histiocytes.
Fibroblast origin
This theory is supported by substantial evidence: MFH
cells expressed mesenchymal antigens (84,85,88). Injec-
tion of DMBA into the knee-joint cavity of rats may induce
MFHs and fibrosarcomas or synovial sarcomas in and
around the joint (93,94). After several recurrences, fibro-
sarcoma may transform into MFH (95). Fibrosarcoma cells
(RFS ) derived from a cadmium-induced fibrosarcoma of
rat, and RFS cells in different subcultures produced
MFH and fibrosarcoma in nude mice and baby rats
(95). Non-transformed and transformed fibroblast-like
mouse embryo cells can be induced to differentiate into
macrophages or histiocytes in a medium supplemented
with human plasma (96). These findings demonstrated
that histiocyte-like cells could result from transdiffer-
entiation of neoplastic fibroblasts.
Other origins
The dedifferentiated components of dedifferentiated sar-
coma (e.g. dedifferentiated liposarcoma, dedifferentiated
chondrosarcoma and dedifferentiated leiomyosarcoma)
and sarcomatous cells of carcinosarcoma, e.g. sarcoma-
tous carcinoma of lung, kidney and prostate and carci-
nosarcoma of breasts, usually look like MFH or
fibrosarcoma (97±105). In addition, the individual case of
malignant melanoma, gliosarcoma and malignant lym-
phoma, has the same appearance as MFH on microscopic
or even electron-microscopic examination (106±108).
Transdifferentiation of neoplastic cells 661
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2001 Harcourt Publishers Ltd Medical Hypotheses (2001) 57(5), 655±666
Karyotype progression of MFH
The karyotype of MFH is far more complex than that of
fibrosarcoma. Cytogenetic evidence of clonal evolution
has been found in some tumors (109). More than half the
tumors were near triploid or near tetraploid, some were
hyperdiploid and even hypodiploid (110). The tumors
develop through acquisition of structural aberrations and
chromosome loss or through gain of a chromosome (111).
Ring, dicentric- and telomeric-associated chromosomes
seem to represent early events in the development of
MFH (109,112,113). Sometimes, the presence of ring
chromosomes is the sole cytogenetic aberration of myxoid
MFH (112,113), as well as the sole consistent chro-
mosomal alteration of well-differentiated liposarcoma
and dedifferentiated liposarcoma with area of MFH ele-
ments (114±116). Ring, dicentric- and telomeric-associ-
ated chromosomes result from telomeric erosion and
are highly unstable, leading to further breakage and
fusion (117).
Genberg et al. established two cell lines from two sub-
sequent recurrences of MHF with identical marker chro-
mosome in common. The U-2149 cell line from the second
recurrence consisted of mainly fibroblast-like cells. The U-
2197 cell line from the third recurrence was composed of
mainly histiocyte-like cells. Based on their data, Genberg
et al. explained the appearance of histiocyte-like cells in
MFH as a consequence of chromosomal progression (118).
APOPTOSIS AND TRANSDIFFERENTIATION
Apoptosis is a universal cellular suicide pathway in
normal elimination and development. Disruption of this
normal process resulting in illegitimate cell survival can
facilitate cancer development and progression.
In histological tumor material apoptotic index (AI) may
be used as a measure of the extent of apoptosis. Most often
AI is defined as a percentage of apoptotic cells and bodies
per total number of tumor cells. A consistent feature in
many studies is the positive correlation or association
between apoptosis and proliferation. In general, rapidly
growing tumors have a greater degree of apoptosis than
relatively indolent ones. Some investigators have begun
investigating the correlation between apoptosis and neo-
plastic transdifferentiation.
The Bcl-2 family and apoptosis in synovial sarcoma
The very recent report of Antonescu et al. (119) indicated
that the monophasic types of synovial sarcoma (with SYT-
SSX2) have a significantly higher mean and median ki-67
labeling index than biphasic types (with SYT-SSX1) (119),
and apoptosis as assessed by TUNEL was rarely observed
in both types, consistent with prominent expression of the
anti-apoptosis protein Bcl-2 in almost all cases. Bcl-2 pro-
tein expression was strong in spindle cells in contrast to
the weak or negative reactivity observed in epithelial cells.
Bcl-2-positive spindle cells consistently surrounded the
negative epithelial elements, a pattern confirmed by the
studies of Antonescu et al. and other investigators (119).
The spindle and adenomatous elements in biphasic syno-
vial sarcoma may be analogous to the undifferentiated
and well-differentiated elements of carcinoma, confirming
that bcl-2 protein expression is indeed different between
two areas of the biphasic tumor.
p53 mutation or inactivation, and apoptosis in MFH
The p53 tumor-suppressor gene is the most commonly
mutated gene in human cancers. Two biological functions
are attributed to p53: regulation of cell cycle progression
after stress, and regulation of apoptosis.
Some evidence indicates that, although p53 mutations
are unlikely to be the primary cause, they may exacerbate
chromosome instability (120). Pilotti et al. investigated
p53 and MDM2 over-expression in 98 lipomatous tumors
by immunocytochemistry, as well as by molecular and
cytogenetic analysis (121). Among the 74 cases of lipo-
sarcomas, 14 cases were of the dedifferentiated subtype
in which the differentiated component was well
differentiated, while the dedifferentiated area had MFH
features in 13 cases. The results show that, in the retro-
peritoneal well-differentiated±dedifferentiated group,
MDM2-mediated inactivation of p53 could be related to
the mechanism of transdifferentiation, while, in the non-
retroperitoneal WD-DD group, the Tp53 mutations appear
to correlate with the dedifferentiation process. Hisaoka
et al. studied eight cases of dedifferentiated liposarcoma
with myxoid MFH areas (122). The clinicopathologic,
cytogenetic and molecular features showed that the dif-
ferentiated portion of tumors was more closely related
to well-differentiated liposarcoma rather than to ordinary
myxoid liposarcoma, while the dedifferentiated part
was myxoid MFH. The myxoid portions frequently
showed a higher proliferative activity, and more MDM-2
and p53-positive tumor cells than in well-differentiated
areas. Hisaoka et al. claimed that an altered p53 pathway,
including p53 gene mutations and MDM-2-mediated
inactivation of p53, may play a role in tumorigenesis of
this myxoid subtype of liposarcoma and its progression
(dedifferentiation) toward conversion into myxoid
MFH (122).
CONCLUSION
Differentiation disturbance of cancer cells should include
not only undifferentiation and dedifferentiation, but also
662 Zhang et al.
Medical Hypotheses (2001) 57(5), 655±666
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2001 Harcourt Publishers Ltd
transdifferentiation. A spectrum of phenotypic features
has been identified in various embryonal carcinoma cells,
which resemble normal embryonic cells at different stages
of development (123). Just like embryonal carcinoma,
most cancers are similar in phenotype to their normal
forebears, but lower in differentiation, e.g. dedifferenti-
ation or even undifferentiation. On the other hand, in
some tumors, as compared to their normal progenitor
cells, the morphophenotypes of tumor cells are converted
into other types by so-called transdifferentiation.
The pathogenesis and progression of neoplasm are
closely associated with genetic instabilities, including sub-
tle sequence changes, alteration in chromosome number,
chromosome translocation and gene amplification (120).
Genetic instabilities are the basis of neoplastic dediffer-
entiation and transdifferentiation. Neoplastic epithelial±
epithelial transition or neoplastic epithelial±mesenchymal
transition may be simply the result of subtle sequence
changes and alteration in extracellular matrix molecules
or stimulation by growth factors, via regulation of cell
proliferation, differentiation and programmed cell death.
As to neoplastic mesenchymal±epithelial transition in
synovial sarcoma and mesenchymal±neural transdiffer-
entiation in Ewing's/pPNET, chromosome translocations
(gene rearrangements) are crucial for transdifferentiation.
The histological origin of some groups of neoplasms
has been debated for decades. Debated tumors include:
multidirectional differentiation tumors; tumors with the
characteristic phenotype of a certain tissue occurring in
an organ foreign to such tissue, e.g. meningioma in lung;
and tumors with a phenotype dissimilar to any type of
normal tissue, e.g. alveolar soft part sarcoma. The histo-
logical appearances of these tumors may result from
transdifferentiation of certain neoplastic cells, and their
histogenesis may be resolved at the cytogenetical and
molecular levels.
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