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Advances in


Volume 98

Page 139

in growth stimulation is seen when insulin is added to serum‐starved quies-
cent cells (Evans et al., 1974). The serum‐starved cells exhibit few microvilli
at their surface, butwithin an hour of insulin additionmicrovilli appear at the
surface in large numbers, along with subcellular organization characteristic
of cells in exponential growth.
Contact‐inhibited confluent cells are limited in their movement and in

surface activity (Abercrombie and Ambrose, 1958). It had been proposed
that contact inhibition of growth is mediated by the establishment of GJC
and exchange of metabolites between the cells (Loewenstein and Penn,
1967). The alternative possibility is that the simple reduction of membrane
activity in confluent cultures is sufficient to account for the inhibition. That
the latter is indeed the case was strongly supported by demonstrations that
the addition of surface membranes isolated from nontransformed cells to
nonconfluent cells imitated the effects of contact between living cells in
confluent cultures. A surface membrane‐enriched fraction of mouse 3T3
fibroblasts added to a sparse living culture of the same cells inhibited the
rate of DNA synthesis (Wittenberger and Glaser, 1977). It had no effect
on transformed 3T3 cells. Glutaraldehyde‐fixed plasma membranes of con-
fluent human embryonal lung fibroblasts inhibited the growth of sparsely
seeded lung fibroblasts (Wieser et al., 1985). The inhibitory effects were
abolished by those treatments of the membranes which inhibit the synthesis
of the oligosaccharides of glycoproteins or enzymatically destroy them,
indicating that cell growth is inhibited by specific cell–cell contact. Some
of the molecular reactants in this process are membrane glycoproteins with
asparagine‐linked oligosaccharides (Wieser et al., 1985).
Plasma membrane purified from adult rat liver inhibited growth‐related

activities of low‐density monolayer cultures of mature rat hepatocytes
(Nakamura et al., 1983). The same preparations stimulated production of
hepatocyte‐specific enzymes characteristic of the differentiated state, just as
confluence among live cells did. Specific differentiated functions and mor-
phology of adult rat hepatocytes can be maintained up to 8 weeks in vitro
only when they are cultured in the presence of rat liver epithelial cells, which
are presumably derived from primitive biliary cells (Mesnil et al., 1987).
When the primary hepatocytes are cultured alone they lose the differen-
tiated state in 2–3 days. Contact between the hepatocytes and the biliary
epithelial cells of the liver is required to maintain the differentiated function
of the former. Although there was increasing GJC with time among hepa-
tocytes themselves in cocultures, and GJC was high throughout the experi-
ment among liver biliary cells themselves in the cocultures, there was no
GJC between the two cell types at any time during the culture period.
The results indicate that the maintenance of hepatocyte‐specific functions
requires intercellular contact, but not GJC, of molecules up to 1000 Da.

128 Harry Rubin

Page 140

It is possible, however, that GJC among the hepatocytes is necessary for
transmission of the signal originating from the biliary cell membranes.
Normal cells in culture must attach to the surface of the dish in order to

proliferate. They fail to multiply when suspended in semisolid medium or in
liquid medium over a surface that does not allow attachment. If a narrow
strip of cells is removed from a confluent, contact‐inhibited culture, cells
remaining on the edge migrate on the bared surface and proliferate rapidly
until the gap is filled (Gurney, 1969). These results and others (O’Neill et al.,
1986) suggest that physical stress on the cell membrane in addition to the
presence of serum growth factors is a component of proliferation. It has
long been known that cells in certain tissues respond to mechanical signals.
For example, mechanosensitive cells in bone, such as osteoblasts, osteo-
clasts, osteocytes, and cells of the vasculature are so placed in the tissue to
react to strain, stress, and pressure (Rubin et al., 2006). The sensations of
touch and hearing are generated by mechanical stress, and other examples
have been found in bacteria, worms, flies, mice, and humans (Kung, 2005).
The proteins of mechanosensitive ion channels sense forces from the lipid
bilayer which open and close the channels. Given the presence of such
arrangements throughout the evolutionary scale of organisms, it is not
unlikely they contribute to the necessity of cell attachment for growth of
vertebrate cells in culture, and may well be involved in regulation of tissue
function, as in the examples cited above.


The primary role of the cell membrane in regulation of proliferation, partic-
ularly with regard to contact inhibition, raises the question whether surround-
ing neoplastic cells with normal cells of the same type could reverse neoplastic
behavior. A relevant consideration is that the mutual adhesiveness of papillo-
ma cells and of carcinoma cells is slightly less and substantially less, respective-
ly, than that of their normal counterparts (Table II; Coman, 1944). It has long
been known that transformation of fibroblasts by infection with RNA and
DNA tumor viruses could be prevented or reversed by surrounding single cells
with contact‐inhibited normal fibroblasts (Rubin, 1960; Stoker, 1964; Stoker
et al., 1966) although such reversal is only possible in the case of some RNA
viruses in the presence of high concentrations of serum in the medium (Rubin,
1960). Related observations have beenmade for fibroblasts transformed spon-
taneously (Rubin, 1994) as well as by treatment with chemical carcinogens or
ultraviolet light (Bertram, 1977; Herschman and Brankow, 1986).

Ordered Heterogeneity and Cancer 129

Page 278

Polyoma protein, 2

Polyomavirus (PyV), 70
Polyunsaturated fatty acid (PUFA)

profile, 160

Pontic mice, 57

Pristane, 30
Proapoptotic genes mutations, 4

Programmed cell death, 4

chemotherapeutic-induced, 164

immune induced, 161–162
oncogenes and, 5

plasma membrane fluidity and, 151,

radiation induced, 162–164

Progressive morphogenesis, in organisms

cell–cell adhesion, 122–125

cell dissociation and reassociation,

contact inhibition of cells, 126–127

role of tissue size, 119–120

Prolyl-4-hydroxylase of collagen type II
[� (II)PH], 237

Promoter methylation, in lactoferrin (LF)

transfectants, 11
Promyelocytes, 194

Proteasome inhibitor (PS-341), 209

Protein tyrosine kinases (PTKs), 192

Proteoglycans (PGs), 224, 226
Proteolytic enzymes, 230–233

Proteus (Morganella) morganii (PM), 35, 39
Pyrenedecanoic acid ratio (IE/IM), 156

Radiation-induced cell death, 162–164

Radioimmunoassays, 70, 83

R36a PnC, 34–37
R36A Streptococcus pneumoniae, teichoic

acid of, 39

Reactive oxygen species (ROS), 158, 172,

227, 230–233
Reticular cells, 19

Retinoic acid response element (RARE), 194

Retinoic acid syndrome (RAS), 194

Retinoids, 193–195
synthetic, 157

Reverse transcription-polymerase chain

reaction (RT-PCR), 202
Ribitol phosphate, 37

RIII tumor cultures, 69

R-115777 inhibitors, 209

Rous sarcoma virus (RSV), 70

R-verapamil, 168

Salmonella species, 21, 39

antibodies active against, 21–22

Sarcoma cells, 126
Seitz filters, 67

Sepharose polymers, 127

Serotonin, 23
Shanghai Institute of Hematology (SIH), 193

Signal transducers and activators of

transcription (STAT) proteins, 208

Simultaneous detection, hybridization
techniques, 83

Somatic cells, 2

Somatic hybrid studies, of tumor cells, 8–9

Somatic mutation, in tumor biology, 61
Sphingomyelinases (SMases), 158

activation of, 171

Sphingomyelins, 154–155, 165

S63 protein, 34, 36
Staphylococcus aureus bacteria, 29
Static membrane phase, 155

Stewart’s National Cancer Institute (NCI)
Division of Pathology, 63

Streptococcus pneumoniae, 39
Streptolysin O, 34

SuGen inhibitors, 207
Susceptibility window, the, 73

SV40 protein, 2, 238

Syndromic proteins, 161

Tamoxifen, 158, 168

Tauroursodeoxycholic acid (TUDCA), 174

T cells release lymphokines, 71
TEPC15 idiotope, 37

Tetrandrine, 168

Thomas, Lewis, 2

age-dependent changes, 225–227

and developmental biology, 119–120

T15 myeloma protein, 40

T protein, 73
Treatment sensitive tumors, 5

Trypan blue, 228

Tuberculoproteins, 29
Tumor clonality, 91–92

Index 267

Page 279

Tumor necrosis factor (TNF)-related

receptors, 170
Tumor suppressor gene clusters, 13

TWIST gene, 245–246

U937 cells, 203

Ultraviolet (UV)-C irradiation, 157

Ursodeoxycholic acid (UDCA), 174

VEGF gene, 13
VH polypeptides, 43
Vinca-alcaloids, 157

Vincristine, 170

Viral superantigen (vSAG), 74

Virus Cancer Program, 82–83
Virus-like particles (VLP), 69

von Hippel-Lindau gene 1 (VHL1), 12
V� T-cell receptors, 71–73

Waldeyer’s principle, of direct continuity, 59

Water-in-oil emulsions, 28

Wnt1 gene, 85
wnt oncogene, 62
Woglom’s 1913 treatise, 61

Wright, James H., 19

Xenopus blastula, 120
Xeroderma pigmentosum (XP), 4

X-irradiation, 5, 127

X-linked recessive alleles, 92
X-ray induced thymic leukemogenesis, 23

XRPC25 protein, 38

X5563 subcutaneous tumors, 25–26, 45

X5647 subcutaneous tumors, 25–26

Ying-Yang 1 (YY1), transcription

factor, 170
YTIYVIAL sequence, 247

Zinder report, 82

268 Index

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