Medical Hypotheses (2006) 66, 76–83

http://intl.elsevierhealth.com/journals/mehy

The cell clone ecology hypothesis and the

cell fusion model of cancer progression
and metastasis: History and experimental support
George E. Parris *

9601 Warfield Road, Gaithersburg, MD 20882, United States

Received 2 August 2005; accepted 4 August 2005

Summary The two-stage initiation–progression model of cancer is widely accepted. Although mutations explain
initiation of neoplasia, the assumption that mutations are responsible for progression of neoplasia to cancer appears to
have little experimental support. The ‘‘cell clone ecology hypothesis’’ explains why neoplasia evolve and the ‘‘cell fusion
model of cancer progression and metastasis’’ describes how they evolve into clinically significant tumors. A brief history of
important concepts and experiments is provided. Clinically significant cancers are effectively new parasite species that
live, expand and evolve within the host. It is hypothesized that survival and fate of the parasite clones called ‘‘cancer’’ are
governed by the principles of ecology. It is argued that while mutations or aneuploidy (asexual reproduction) can result in
transient/self-limiting neoplasia, neither of these asexual modes of forming new karyotypes can maintain the ecologically
fit parasites that develop into clinically significant cancer. Mutations and/or unstable genomes (aneuploidy) progressively
degrade cell lines and if only these mechanisms were at work, neoplasia would spontaneously become extinct or benign
(enfeebled) before reaching clinical significance (an example of ‘‘Muller’s ratchet’’). In the cell fusion model of (clinically
significant) cancer progression and metastasis, cell–cell fusion is the essential element allowing normal cells or
(transient) neoplasia to evolve into clinically significant cancers. Cell–cell fusion is required for producing and sustaining
clinically significant cancer because it provides a sex-like mode of reproduction essential for an ecologically fit parasite
organism. Cell–cell fusion provides the opportunity needed for tumors to rejuvenate cell lines containing abnormal
genomes and rapidly evolve to acquire dramatically aggressive traits such as metastasis. Indeed, metastasis appears to
require cell–cell fusion. Cell–cell fusion also partially overcomes erosion of teleomeres during clone expansion and
allows the essential elements of a tumorigenic genome to hide from chemotherapy as recessive traits in cells with normal
phenotypes and re-emerge (by cell–cell fusion) as a new cancer after the phenotypically cancerous cells have been
eradicated by classical chemotherapy. Eradication of the cancer parasite cannot be routinely achieved by classical toxic
chemotherapy alone or even by chemotherapy augmented with techniques needed to overcome anti-apoptotic traits of
cancer cells. Direct chemical intervention against cell–cell fusion concurrent with classical toxic chemotherapy holds a
promise of preventing re-lapse of the disease. Intervention against cell–cell fusion may also directly suppress metastasis
based on the model presented here. The paper also summarizes work on the cell surface glycoprotein CD44 that implicates
it as a key element in cell–cell fusion and hence cancer.
c 2005 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: +1 301 963 7037.

E-mail address: antimony_121@hotmail.com.


0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2005.08.009
The cell clone ecology hypothesis and the cell fusion model of cancer progression
Introduction and history
It was recently argued [1] that cell clone ecology
determines the fate of neoplasia, which may be-
come extinct, may never significantly expand, or
which may evolve into clinically significant can-
cers. Mutations and/or aneuploidy can produce via-
ble abnormal cells that found cell lines that expand
into neoplasia. Some of these neoplasia (i.e., pre-
cancerous) remain under the control of the host
and some become cancerous (i.e., immortal and
free from the cell cycle control of the host). The
cancerous neoplasia evolve as though they were
separate parasite species in competition with host
cells and each other. However, if de novo muta-
tions (i.e., changes in DNA sequence) and aneu-
ploidy (i.e., adding and deleting chromosomes
from the individual parent cell) were the only
modes of genome modification available, the cell
lines that make up the (pre-cancerous or cancer-
ous) neoplasia are very likely to degenerate and be-
come progressively less competitive with the host
cells. Thus, the parasite neoplasia would rarely be-
come palpable tumors and would generally become
extinct, rather than be observed as a disease called
‘‘cancer.’’ On ecological grounds, it was hypothe-
sized [1] that the evolution of successful parasite
clones is dependent upon periodically refreshing
its genome by cell–cell fusion. It was also hypoth-
esized that viruses that catalyze cell–cell fusion
might play a large role in progression of neoplasia
into cancer [2]; not because they cause mutations
in the host genome, but rather because they facil-
itate cell–cell fusion. Through a sex-like process of
cell–cell fusion and neosis [3,4], the parasite neo-
plasia are able to overcome debilitating mutations
(including depleted teleomeres caused by exten-
sive clone expansion) and chromosome deficits by
acquiring normal chromosomes (from normal
cells). It was pointed out that successful eradica-
tion of clinically significant cancer will require pre-
vention of the sex-like cell fusion cycle that allows
for sequestration of oncogenes in cells with normal
phenotypes and rapid evolution of the parasite
clones.
This hypothesis [1] was proposed without refer-
ence to experimental observations of cell–cell fu-
sion (i.e., a mode of sexual reproduction)
converting neoplasia into aggressive cancers. This
oversight can be explained by the fact that the
two principal competing hypotheses (i.e., muta-
tions and unstable genome/aneuploidy) have gen-
erally ignored the startling evidence of cell–cell
fusion found in most cancers or treated cell–cell
fusion as an unimportant artifact. A search of the
77
literature, however, has uncovered a series of
remarkable reports scattered in different fields
over a period of 25 years. If these reports had been
concentrated in space and time, the importance of
cell–cell fusion in successful progression of cancer
would likely be regarded as obvious. In this report,
the history and experimental support for cell–cell
fusion as the important element in progression of
neoplasia to clinically significant cancer (i.e., the
disease ‘‘cancer’’) is summarized (see Fig. 1).
The essential ideas (the importance of cell–cell
fusion and sexual reproduction on cancer fitness
and cell clone ecology) have been independently
proposed by Bremermann [5] in 1979, Qian [6] in
1993, and by Parris [1] in 2005. Shaw [7] suggested
that cancer is caused by the fusion of host cells
with bacteria; an idea for which no experimental
support has been found. As early as 1983, Hart [8]
noticed that tumor (melanoma) cell lines under-
went spontaneous fusion especially when clones
were cultured in constrained space [9] and that
the new cells derived from these unions gave rise
to progression of the neoplasia to more aggressive
forms. He immediately articulated two fundamen-
tal points related to this hypothesis: (i) cell–cell
fusion leads to polyploidy, which increases the
effective genomic instability leading to aneuploid
variants, and (ii) cell–cell fusion provides a mech-
anism for sequestration (and re-emergence) of
oncogenes as recessive traits in phenotypically nor-
mal cells. Hart [8], however, did not specifically
address the ecological significance of sexual repro-
duction in cancer clones.
In 1992, Munzarova et al. [10] posed the ques-
tion ‘‘Are advanced malignant melanoma cells hy-
brids between melanocytes and macrophages?’’
Pawelek [11,12] commented on this question in
1993 and with various co-authors has published a
number of papers (1998–2005, see below) demon-
strating that fusion hybrids between primary mela-
noma tumors or lymphoma tumors and leukocytes
frequently have enhanced potential for metastasis.
Modification of the initiation–
progression model of cancer
Mutations and unstable genomes generally
lead cell lines to extinction, while cell–cell
fusions lead neoplasia to cancer
In the usual discussion of the initiation–progression
model of cancer, cancer is ‘‘initiated’’ by muta-
tions and ‘‘progression’’ is attributed to continued
78
Figure 1 Cancer progression (evolution and extinction of abnormal cells).
accumulation of mutations. Clearly, progression is
associated with changes in the genome of the can-
cerous cells, but the point of the cell–cell fusion
hypothesis discussed here [1,2] is that cell fusion
(a sexual event) is much more efficient that simple
mutations (asexual events) at providing the geno-
mic changes. Indeed, there are experimental
observations and theoretical considerations that
suggest that mutations (alone or with incipient
aneuploidy) can only produce self-limiting neopla-
sia. That is, mutations (usually with aneuploidy)
initiate cancers but cannot cause them to progress
to clinically significant tumors because of the limi-
tations of asexual reproduction. On the other hand,
it seems probable (based on information provided
below) that cell–cell fusion will occur among the
mutated cell population and this (i.e., sexual
reproduction) will frequently lead to clinically sig-
nificant cancer.
Evidence that mutations alone usually do not
facilitate progression of neoplasia to clinically sig-
nificant cancer is provided by diseases caused by
faulty DNA repair including xeroderma pigmento-
sum (XP), Cockayne’s syndrome, trichothiodys-
trophy and others. Victims of these diseases
acquire many non-cancerous neoplasia. Although
Parris
XP elevates skin cancer risk (i.e., incidence) by
1000-fold, the rate of progression (i.e., evolution)
of the tumors seems to be normal. If mutations alone
were sufficient to cause progression of tumors from
small neoplasia to clinically significant cancer, pro-
gression of cancer in XP cases should be exception-
ally fast. It is particularly interesting that although
UV light readily mutates DNA in cells from Cocka-
yne’s syndrome and trichothiodystrophy, these dis-
eases do not show elevated incidence of skin
cancer [13]. The observation [14] of a benign,
repair-deficient cell line from a victim of XP sponta-
neously changing into an aneuploid, cancerous,
repair-competent cell line in vitro also suggests that
mutations per se do not account for clinically signif-
icant cancer formation and points toward cell–cell
fusion as the important element. Moreover, there
has been an analysis of DNA ploidy in normal skin
and various tumors of an XP patient [15].
(i) In normal skin protected from the sun, the
cells were normal (diploid).
(ii) In normal-appearing skin exposed to the sun,
there were many more hyperdiploid cells.
(iii) In actinic keratoses, there were even more
hyperdiploid cells.
The cell clone ecology hypothesis and the cell fusion model of cancer progression
(iv) In the primary squamous cell carcinoma,
there were numerous hyperdiploid cells and
aneuploid cells that were apparently derived
from the hyperdiploid cells.
(v) Over time, the fraction of aneuploid cells
increased in the squamous cell carcinoma.
(vi) In the lymph node metastasis from the pri-
mary squamous cell carcinoma; the principal
cell type was aneuploid.
Finally, Milo et al. [16] reported from their work
with chemical mutagens and carcinogens that non-
malignant tumor clones can be converted to malig-
nant phenotypes without acquiring additional
mutations. Conversely, exposure of transformed
cells to continuous doses of mutagens did not
accelerate progression of tumors. All these obser-
vations are consistent with initiation of the cancer
by mutations and progression via cell–cell fusion to
hyperdiploid cells, which generate aggressive
aneuploid clones.
As noted in a previous publication [1], inherently
unstable genomes cannot reproduce themselves
and hence cannot be ecologically successful.
Unstable genomes quickly evolve to stable gen-
omes, which may be aneuploid and which may
meet the basic requirements for cancer (i.e., inde-
pendent evolution). But, without infusion of chro-
mosomes from other cells (through cell–cell
fusion), chromosomes and genes that have been
lost cannot be replaced. Further mis-assortment
of the available chromosomes will ultimately result
in more lost information and ultimately extinction.
In summary, neither mutations nor aneuploidy
(i.e., unstable genomes) allow a cell line to ‘‘fix
mistakes’’ (i.e., if a gene is damaged or a chromo-
some is lost, that information/capability cannot
be recovered through further mutations or aneu-
ploidy alone). Although a few random mutations or
mis-segregations of chromosomes may produce a
species phenotype that is able to expand into a
small neoplasm, further ‘‘asexual genomic events’’
(at the gene or the chromosome level) are more
likely to disable the new species (sending it to
extinction) than enable the new species to thrive.
It is relevant that Gatenby and co-workers [17–
24] have constructed mathematical models of can-
cer based on information degradation during tumor
evolution. The evolutionary model summarized in
2003 [22] is consistent with the two-phase model
described here (see Fig. 1). Namely, the first phase
is limited by progressive information degradation
(mutations and aneuploidy) results in only small tu-
mors that are in equilibrium with the host tissue.
The second phase of expansion to clinical signifi-
cance requires the ability to evolve. Gatenby and
79
co-workers, however, do not seem to address the
mechanics of evolution and only describe it as a
‘‘mutator phenotype’’ [22]. Subsequently [24],
they envision ‘‘Darwinian somatic ecology’’ as a
method of limiting information degradation caused
by mutations. The degradation of fitness in asexual
populations due to mutations (Muller’s ratchet) has
been modeled under various scenarios [25–27] and
subjected to experimental observations. Although
selection for fitness may prolong the existence of
an asexual lineage, the equations are sensitive to
a number of variables [25] and it is not clear that
stability can be reached in most real systems with
purely asexual reproduction.
On the other hand [1], sexual events (cell–cell
fusion and neosis) allow resorting of chromosomes
among abnormal cells and normal cells. Sexual
reproduction may generate a new (i.e., more eco-
logically successful) parasite cell line that produces
a more aggressive cancer. Sexual reproduction
has been shown to be essential to successful sur-
vival and evolution of most species [28,29], and
the free-evolving parasite cell clones known as
‘‘cancer’’ are not exceptions.
Sexual reproduction not only allows for faster
evolution, it allows abnormal phenotypes to disap-
pear entirely while keeping the tumorigenic traits
alive as recessive alleles. This should be consid-
ered when developing anti-cancer chemotherapies
therapies that target specific phenotypes. An
example is provided by Makarovskiy et al. [30]
who studied the aftermath of chemotherapy on
prostate cancer cells. In one cell line, chemother-
apy led to growth arrest, followed by formation of
multinucleated giant cells. The authors attributed
the multinuclear cells to karyokinesis, rather than
cell fusion, and the agent used is known to inter-
fere with mitosis. Cell fusion, however, more read-
ily explains the observed size of the multinuclear
cells. Regardless, under continued exposure to
the chemotherapeutic agent (required for selec-
tions of resistant phenotypes), the multinuclear
giant cells gave rise to new cell clones that were
similar to the parental lines except that they
exhibited resistance to the chemotherapeutic
agent.
Evidence that enhanced tumorigenic
phenotypes can result from fusion of
various types of cells
There are numerous examples in the literature of
progression of cancer (acquisition of a more
aggressive phenotype) through cell–cell fusion.
80
The work of Hart [8,9] has been mentioned. De
Baetselier et al. [31,32], Larizza et al. [33], Miller
and co-workers [34,35] and Fortuna et al. [36,37]
made similar observations that cell–cell fusion
can lead to aggressive and/or metastatic
phenotypes.
The most extensive and systematic work has
been done by Pawelek, Chakraborty and co-work-
ers on melanoma. As mentioned above, Pawelek
seems to have become interested in the role of cell
fusion in cancer progression circa 1993 [11]. This
team has tested various elements of the hypothe-
sis: In 1999, they [38] reported that most hybrids
that formed between a weakly metastatic mouse
melanoma and normal mouse or human macro-
phages were more prone to metastasis than the
parent tumor. The propensity for the (hybrid) neo-
plasm to metastasize generally paralleled the de-
gree of melanin production [38,39]. Moreover,
melanogenesis and metastasis were both regulated
by N-link glycosylation of glycoproteins [39–41]. In
2000, they [42] demonstrated that the remote
metastases derived from a primary tumor, indeed,
mainly consisted of (frequently polyploidy)
host · tumor hybrids (also see reference [15])
and, in 2001, they [43] showed that monocyte
genes are expressed in monocyte · melanoma
fusion hybrids.
Summary of evidence for the
essentiality of sexual reproduction
(through cell–cell fusion) in progression
of neoplasia to cancer
Although mutations are efficient at generating
abnormal parasite cell clones that escape from
the control of the host organism, there is little
evidence that mutations alone or with incipient
aneuploidy can facilitate progression of small
parasite clones to clinically significant cancers.
Muller’s ratchet (progressive information loss) en-
sures that asexual species will become extinct or
reach a steady state. On the other hand, cell–cell
fusion (tumor · host) provides a sexual mode of
reproduction that does facilitate rapid and sus-
tained evolution of parasite clones that is consis-
tent with the observed process of tumor
progression.
The practical implications of this idea are very
important. Although the rate of tumor formation
is likely governed by mutations, the rate of clini-
cally significant cancer development is likely gov-
erned by cell–cell fusion. Thus, therapeutic
strategy should emphasize prevention of cell–cell
Parris
fusion concurrent with targeted destruction of
cells displaying a cancerous phenotype. Even
though chemotherapy might kill all the cells with
the cancer phenotype, recurrence is possible if
cells carrying recessive cancer traits can fuse.
Moreover, merely preventing cell–cell fusion of
parasite clones would be expected to cause pro-
gressive remission of tumors as Muller’s ratchet
brings the asexually reproducing clones to
extinction.
It is speculative whether or not cell–cell fusion
alone (without any gene mutations) could initiate
tumors. Whether or not a cancerous phenotype
can be achieved without mutations depends en-
tirely upon what genes are on what chromosomes.
Some of the observations such as the viral causa-
tion of cervical cancer [2] suggest that it might
be possible.
If the hypothesis discussed here is correct, it
behooves cancer researchers to closely examine
the mechanism of cell–cell fusion. In examining
the information discussed below, an additional
hypothesis has been formulated regarding the
mechanism(s) of metastasis an invasion, which
are typically part of the progression of cancer.
The focus on cell surface glycoproteins,
especially CD44
With the link between cell fusion and metastasis
firmly established, the Pawelek–Chakraborty team
has continued investigating the phenotype that
facilitates metastasis [39,44,45]. Their work on
N-link glycosylation [39] has led to beta 1,6-
branched polylactosamines produced by beta
1,6-N-acetyl-glucosaminyltransferase V (GnT-V)
[44,45]. Up-regulation of this enzyme (at both the
mRNA and protein level) correlates with metastatic
potential [45–47]. This observation leads to the
work of Vignery circa 1998 [47,48] and East and Hart
circa 1993 [49,50] who independently identified
CD44 as a key player in melanoma metastasis and
cell–cell fusion.
Although there are many surface glycoproteins
that have been studied in connection with virus-
cell and cell–cell fusion processes, CD44 appears
to be a very important player in evolution and
metastasis of tumors especially when the fusion in-
volves mononuclear phagocytes [47,48]. CD44 has
been studied extensively by a number of workers
[51] with interests in various fields. The CD44 gene,
located in the human genome at 11p13, has about
ten transcription variants; and in some abnormal
cells (tumors), even introns are transcribed. The
principal form of the protein has been described
The cell clone ecology hypothesis and the cell fusion model of cancer progression 81

as having three domains (external, trans-

membrane and cytoplasmic). The N-terminal end
of the protein is external, and among the con-
served sites in the external domain, there are five
asparagine (Asn) residues, which are subject to N-
glycosylation. The degree of N-glycosylation ap-
pears to be more important than the splice variant
in determining the binding properties of the pro-
tein. Thus, the binding properties of the protein
are regulated in the specific cell by activity of
the beta 1,6-N-acetyl-glucosaminyltransferase V
(GnT-V) [43,44], as discussed above. It must be
acknowledged that the role of CD44 is likely only
a part of a larger picture. For example, in some
cases, destruction of the extra-cellular matrix by
matrix metalloproteinases may provide the mecha-
nism for mobilization of tumor cells.
As pointed out in an earlier publication [2]
viruses catalyze cell–cell fusion. The literature
contains many examples of the effects of N-glyco-
sylation on the function of virus fusion proteins. It
is reasonable to believe that virus-catalyzed cell–
cell fusion works similar to the process described
here involving CD44.
The model of metastasis that seems to be most
consistent with observations (see Fig. 2) is that
normal cells are both held in place and prevented
from fusing by the extra-cellular matrix. The ex-
tra-cellular matrix is composed largely of hyaluro-
nan (HA). HA is a large, negatively charged Figure 2 A model for metastasis.
polysaccharide and has been described as the uni-
versal ‘‘goo’’ that holds tissues together. Cells nor-
mally hold their place in the tissue by latching onto
the polysaccharide with certain classes of their CD44 Expression and hyper-glycosylation
adhesion molecules (e.g., glycoproteins). Among in migrating cell clusters and micro-
these, CD44 is a particularly important receptor metastasis
for HA [52]. The affinity of a cell for HA is governed
by the degree of glycosylation of CD44 (and related In order for metastasis to occur, the migrating cells
molecules). Although affinity of CD44 for HA does must ultimately adhere to and invade remote tis-
not change monotonically as a function of the de- sue sites. It is observed, that clusters of tumor cells
gree of N-glycosylation of the external asparagine (typically 2–6 cells) often form and migrate to-
(Asn) residues, when all the Asn sites are glycosyl- gether [57,58]. It is presumed that these cells are
ated, CD44 (and hence the cell) loses affinity for in direct membrane–membrane contact without
the HA matrix [52–56]. Thus, these hyper-glycosyl- the intervention of HA. These cell clusters are well
ated cells become mobile, and without the HA ma- on their way to cell–cell fusion. Cell–cell fusion
trix bonds, these cells are free to fuse with one can occur during transit or upon adhesion to
another or with normal cells (e.g., monocytes). Fu- specific remote sites (driven by other adhesion
sion of hyper-glycosylated cells may be driven by molecules). When cell–cell fusion occurs, the
nothing more than surface tension effects, e.g., resorting of chromosomes can produce hybrids that
small soap bubbles coalesce into bigger soap do not express hyper-glycosylated CD44, and thus,
bubbles. In summary, over-expression of beta 1,6- adhere to the HA at the new site. It is possible that
N-acetyl-glucosaminyltransferase V (GnT-V) clusters of migrating cells could form around solu-
[44,45] is enough to send melanoma neoplasia off ble fragments of HA, but these clusters should not
into aggressive metastasis (i.e., mobile and sponta- readily undergo cell–cell fusion and such clusters
neously fusing cells) as observed by Chakraborty would not appear to have a propensity to lodge
and Pawelek. at remote sites. A key element in the model of
82
metastasis proposed here is that cell–cell fusion in
transit turns the migrating cells into homing cells.
Mutations involving malformation of CD44, sup-
pression of CD44 synthesis or accelerated destruc-
tion of CD44 (i.e., an overall reduction in
hyaluronan-binding CD44) also should lead to
migrating cells, which might become homing cells
upon cell–cell fusion [59,60].
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