close

Вход

Забыли?

вход по аккаунту

?

632

код для вставкиСкачать
1757
A Festschrift Honoring the 90th Birthday on May 9, 1997, of
Jonathan Evans Rhoads, M.D., Editor Emeritus of Cancer
Cancer special section
A Comparative Review of the Immunobiology of
Murine Neuroblastoma and Human Neuroblastoma
Moritz M. Ziegler, M.D.1
Hiroyuki Ishizu, M.D.2
Eisuke Nagabuchi, M.D.2
Naoyuki Takada, M.D.2
Gajra Arya, M.S.1
BACKGROUND. The prognosis for children with neuroblastoma (NB) remains dismal, in part because of extent of disease at diagnosis as well as resistance of tumors
to conventional therapies. However, human NB exhibits many favorable traits,
including the capability to mature into a more benign form or to regress spontane-
1
Division of Pediatric Surgery and the Children’s Hospital Research Foundation, Children’s
Hospital Medical Center, and the Departments
of Pediatrics and Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
2
Department of Surgery, Hokkaido University,
Sapporo, Japan.
ously. A murine model of disease that could permit eventual genetic manipulation,
so that such beneficial traits could be identified or even augmented, would be
most useful.
METHODS. This report details an analysis of the contemporary study of the tumor
growth, metastases, immunogenicity, and immunotherapy of murine NB and compares it with known patterns of clinical NB.
RESULTS. Striking similarities exist in the local tumor growth and metastatic behaviors of murine and human NB, behaviors that in part may be related to a hosttumor immunologic response. The naturally low expression of class I antigen in
NB, the ability to augment that expression with cytokines, and the phenotype of
the cellular and humoral immune response to NB are strikingly similar in human
and murine hosts. Comparable immunotherapeutic potential exists. There have
been rare and sporadic observations of spontaneous regression of an existing
murine NB, unlike the more predictable regression of Evans Stage IV–S clinical
NB.
CONCLUSIONS. The many similar biologic, physiologic, and immunologic characteristics of human and murine NB make the murine model a valuable adjunctive
aid in furthering our understanding of human disease. Cancer 1997;79:1757–66.
q 1997 American Cancer Society.
KEYWORDS: neuroblastoma, human, murine, tumor, immunobiology.
T
Address for reprints: Moritz M. Ziegler, M.D.,
Department of Surgery, Children’s Hospital
Medical Center, 3333 Burnet Avenue, Cincinnati,
OH 45229-3039.
Received December 4, 1996; revision received
February 7, 1997; accepted February 7, 1997.
en years ago, we reported the utilitarian nature of a murine model
of neuroblastoma (NB) when comparing it with the biologic behavior of human neuroblastoma.1 Because human neuroblastoma remains a childhood cancer with a poor prognosis, yet demonstrates
unusual favorable characteristics of regression and maturation to a
benign form, a model of human disease may shed light on either
tumor-host mechanisms or potential new therapies that may deserve
trial for this otherwise treatment-resistant cancer.
In the last decade, the advent of new treatment models, the use
of analytic techniques to define biologic mechanisms at the molecular
level, and a better understanding of host-tumor immunobiology have
allowed for an improved definition of murine neuroblastoma. This
review summarizes data accrued in the last decade and expands the
base of knowledge defining C-1300 murine neuroblastoma as an effective model of human disease.
q 1997 American Cancer Society
/ 7b55$$1041
04-02-97 14:43:51
cana
W: Cancer
1758
CANCER May 1, 1997 / Volume 79 / Number 9
Tumor Growth Characteristics
Characteristics in humans
Clinical NB is an embryoma originating in primitive
neuroblasts, the origins of which are in the distribution
of neural crest cells. The most frequent locations are
abdominal, suprarenal or para-aortic, thoracic paraspinal, cervical sympathetic chain, or even pelvic or
retro-orbital intracranial sites; that is, primary tumors
are found at any site where cells of the neural crest are
located. The neuroblasts typically form well-oriented
rosettes, and tumor histology demonstrates cellular or
stromal preponderance. Histopathologic characteristics of differentiation, maturation, lymphoid infiltration, calcification, anaplasia, necrosis, mitotic activity,
neuropil, and multinucleated cells have been utilized
in prognostic classifications.2,3 The tumor grows progressively in local sites and has the propensity to invade surrounding tissues, especially enwrapping
nerves and vessels. However, in a given solid tumor,
the majority of cells are in their resting phase.4
Clinical NBs are characterized by several unique
features. The NBs metabolize catecholamines and, as
a result, excrete various markers of tumor activity, including vanillymandelic acid (VMA) or homovanillic
acid (HVA), markers for which quantitative ratios can
indicate tumor differentiation and may therefore even
signify prognosis.5 It is this same excretion that forms
the basis for population screening for NB.6
NBs can spontaneously, or, after therapeutic stimulation by differentiating agents, mature into benign
ganglioneuromas. Benign ganglioneuromas such as
these may occur anywhere, but they are usually localized in the thoracic paraspinal region. The presence
of ganglioneuroma in lymph nodes emphasizes the
original malignant metastatic behavior that the NB
demonstrated before the maturational change occurred.
The most enigmatic behavior of clinical NB is its
spontaneous regression; it is the most common human tumor to undergo such change.6 This is a particularly prevalent feature in Evans Stage IV – S patients.
There is evidence attributing this behavior to an immune mechanism. Beckwith and Perrin demonstrated
that nests of NB cells in the adrenal glands of stillborn
infants occur at a much higher frequency than tumors
in the general population.7 Additional evidence of an
immune mechanism for spontaneous regression is the
report that Stage IV – S NBs express a higher level of
class I MHC antigen than NBs at Stages I – IV.8 Alternate mechanisms that might explain tumor regression
include the ‘‘two-hit’’ theory of oncogenesis described
by Knudson and Meadows,9 a relationship of regression to N-myc oncogene amplification,10 a coexpression of the mRNA for both the TRK gene and the low-
/ 7b55$$1041
04-02-97 14:43:51
cana
FIGURE 1.
Survival of strain A mice after inoculation of 106 murine
neuroblastoma (NB) cells into their flank subcutaneous tissue. C1300-NB
recipients died after progressive local tumor growth,whereas TBJ-NB mice
demonstrated widespread metastases and, as a result, more rapid mortality
(mean survival time [MST], 32.4 vs. 45.9 days).
affinity nerve growth factor (NGF ) receptor,11 and an
alteration of apoptosis.12
Murine characteristics
C1300-NB arose spontaneously from the spinal cord
region in strain A mice almost 50 years ago. It has
previously been demonstrated by in vitro and in vivo
techniques to express tumor antigen. It grows progressively with local invasiveness until the death of the
animal; it can, but rarely does, metastasize; it can be
induced both in vitro and in vivo to mature from a
malignant NB to a benign ganglioneuroma; it metabolizes catecholamines; and there have been rare and
sporadic observations of spontaneous tumor regression1 (Fig. 1).
TBJ-NB is a spontaneously developing clone of
C1300-NB that was first identified at Jackson Laboratories. In contrast to C1300-NB, TBJ-NB grows rapidly
and invasively, metastasizes readily, and results in an
early death for the animal1 (Fig. 1).
Both tumors are small, round-cell sarcomas that
do not typically form rosettes (rosettes characterize
the human tumor). Both tumors can be passed serially
in strain A mice or by serial in vitro passage in tissue
culture.
Like human NB, murine NB solid tumors, whether
primary or metastatic, are composed of cells that are
mostly in the resting stage.1,4 The subtotal resection of
the primary tumor results in rapid proliferative cellular
activity in the residual tumor,13 and the resection of a
W: Cancer
Murine Neuroblastoma as a Disease Model/Ziegler et al.
primary tumor results in similarly enhanced proliferative activity of a remote metastatic focus.14 Such proliferative activity, which occurs earlier than the stressinduced bone marrow proliferation that takes place
during surgery, provides a window for adjuvant postresection chemotherapy.
Catecholamine metabolism in murine NB has previously been reported.1 The levels of dopamine and
norepinephrine urine concentration in tumor-bearing
mice are significantly higher than those measured in
tumor-free control mice.15
Maturation of murine NB has been reported previously. In vitro admixture of C1300-NB with NGF or
retinoic acid results in dendritic outgrowth. We have
previously shown that a combination of cytoreductive
surgery, along with administration of Calmette-Guérin
bacillus (BCG) to the local tumor site, not only retards
tumor growth but also may induce change in tumor
maturation as well.1 The roles of neurotrophins, NGF,
and brain-derived neurotrophic factor (BDNF ), as well
as the role of their signal transducing receptors, trkB,
are currently being studied in vitro in murine NB cell
lines in our laboratory. In human NB lines, the truncated trkB is preferentially expressed in more differentiated tumors. In such trkB-expressing human tumors,
the BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine fashion.11
The spontaneous regression of murine NB has
rarely been observed. Sporadically, we have witnessed
the disappearance of an existing tumor nodule in an
otherwise untreated tumor-bearing mouse. We have
previously reported a tumor transplant experiment in
which clinical Stage IV – S tumor sites were mimicked
in a mouse, and an improved animal survival was seen
for mice with Stage IV – S tumors in contrast to animals
with comparable tumor burdens transplanted to Stage
IV sites.16 This finding has been corroborated by others.17 In addition, in a murine model of liver metastases, in which C1300-NB cells were injected into subcutaneously translocated spleens, animals bearing liver
tumors were continuously infused with interleukin-2
(IL-2) for 14 days. Not only did IL-2 significantly prolong survival, but the tumors in 50% of the animals
disappeared completely after treatment.14 Akin to clinical Stage IV – S patients whose liver tumors spontaneously regressed, these animal livers reverted to a normal histology after IL-2 treatment, without evidence
of either scarring or tumor maturation. Furthermore,
histologic examination of the treated animal livers
showed an early mononuclear cell infiltration within
the metastatic foci; and on phenotypic analysis of
these cells, they were Thy 1.2 positive and asialo GM1
positive, suggesting that they were of natural killer
(NK) or lymphokine-activated killer (LAK) cell origin.14
/ 7b55$$1041
04-02-97 14:43:51
cana
1759
TABLE 1
Tumor Growth and Metastasis 3 Weeks after the Subcutaneous
Inoculation of 106 NB Cells
Valuea
Body weight (g)
Square tumor weight (g)
Incidence of metastasis
Liver
Adrenal glands
Subclavicular lymph nodes
Inguinal lymph nodes
Other lymph nodes
Lung
C1300-NB
(n Å 8)
TBJ-NB
(n Å 8)
P value
20.8
4.1 { 2.1
22.2
5.1 { 1.2
NS
NS
0/8
0/8
6/8
3/8
2/8
0/8
6/8
4/8
8/8
3/8
0/8
1/8
0.003
0.039
NS
NS
NS
NS
NB: neuroblastoma; NS: not significant.
a
Student’s t test.
In an additional series of experiments, the influence
of host age and immunologic maturation on the support of tumor growth and regression was tested. Neonatal animals seemed to support the growth of NB less
well than adults, though the tumor inoculum bestowed specific immunity to subsequent tumor challenge.18 Similarly, maternal immunization has resulted
in an antibody-dependent cellular cytotoxicity reaction to C1300-NB in the offspring.19 Whether such host
immunity contributes to spontaneous regression of
the murine tumor remains uncertain.
Tumor Metastases
Human
Human NB has a characteristic pattern of metastases:
the primary tumor grows aggressively locally, and it
metastasizes to regional lymph nodes, the liver, and,
finally, to bone marrow or bone cortex. Metastatic propensity is typical in NBs in which N-myc oncogene
amplification is present20; the tumors are less mature
and express full-length TRK-B.21 In addition, the expression of the protooncogene bcl-2 is also associated
with unfavorable histology, N-myc amplification, and
malignant tumor progression.22 Other clinical features
relating to metastases include age: patients younger
than 1 year are more prone to tumor distribution in
Stage IV – S sites, namely, skin, liver, and bone marrow;
in older children, metastases more characteristically
occur in bone, bone marrow, and lymph nodes, and
rarely in the retro-orbital venous plexus, where ‘‘black
eyes’’ are produced. Metastates of NB to the central
nervous system (CNS) and lung are rare.
Murine
We have extensively studied the metastatic behavior
of murine NB both in vivo and in vitro (Table 1).
W: Cancer
1760
CANCER May 1, 1997 / Volume 79 / Number 9
FIGURE 2.
An analysis of the relative in vitro invasiveness of C1300NB and TBJ-NB in Boyden chambers, where the penetrating membrane is
Matrigel and the attractant is fibronectin. TBJ-NB demonstrates significantly greater invasiveness.
C1300-NB in strain A mice characteristically grows
progressively until the death of the animal; and in later
stages of tumor growth, it is associated with regional
lymph node metastasis. Central organ metastasis does
not occur, a behavior akin to early stage clinical NB
with favorable prognosis. In sharp contrast, TBJ-NB
also grows aggressively at the site of a local inoculum
of a single-cell suspension, but liver, adrenal gland,
and lymph node metastases are all prevalent behaviors. In rare instances, lung metastases also occur. This
metastatic behavior of the TBJ clone is similar to advanced stage clinical NB. In an in vitro invasion assay
using Matrigel and a fibronectin attractant, the TBJ
was shown to be significantly more invasive than
C1300 tumor (Fig. 2). Similarly, in an in vitro aggregation kinetic assay of the murine NB cell lines, the TBJNB clone remained significantly more dispersed than
its C1300-NB counterpart (Fig. 3). These data support
the conclusion that the two murine NB cell lines differ
in regard to characteristics defining the physical cellular features that influence metastatic behavior.
The neural cell adhesion molecule (NCAM) L1 is
a member of the immunoglobulin superfamily expressed by the CNS, and expression is found in most
CNS tumors, including human NBs.23 Although L1 expression has most often been linked to tumor migration and metastases,24 its expression is seen only in
metastasizing melanomas, but not in the nonmetastasizing melanoma of the neural crest region.25 The exact
mechanistic role of L1 in human or murine NB metastases awaits elucidation. At the molecular level, further
studies of murine tumors have been conducted to determine behaviors that may contribute to a metastatic
phenotype. Northern blot analysis has shown that
/ 7b55$$1041
04-02-97 14:43:51
cana
mRNA of NCAM is equally expressed in both C1300
and TBJ cell lines. However, both N-myc mRNA and
L1 mRNA are expressed to a much greater degree in
the metastasizing TBJ-NB clone (Fig. 4). The N-myc
data is consistent with that seen for human NB, but
the L1 data is of less certain significance.
Flow cytometric FAC scan protein analysis of these
murine NB lines has confirmed that both murine NB
tumor lines express NCAM and MHC-1 antigen protein. Interestingly, the analysis also demonstrates DNA
aneuploid pattern for both C1300-NB and TBJ-NB.
This latter data contrasts with data regarding human
NB, in which patients with early stage disease have
demonstrated a hyperploidy tumor DNA pattern,
whereas advanced stage disease has been associated
with a diploid tumor cell DNA pattern.20
Further analysis of metastatic NB has made use
of a surgical model of liver metastasis by inoculating
C1300-NB cells directly into a subcutaneously translocated spleen. These ‘‘liver metastatic’’ tumors grew
progressively until the animals died, and variations in
the length of survival depended directly on the tumor
inoculum.14 This model has permitted an analysis of
the efficacy of both chemotherapy and immunotherapy in the treatment of a stage of disease that is almost
invariably fatal for humans. Additionally, the model
has permitted an analysis of metastatic tumor kinetics
utilizing bromodeoxyuridine staining. Mice bearing
liver metastases that were subjected to sham operation
demonstrate no increase in their labeling index (LI),
whereas mice that underwent resection of a concomitant subcutaneous tumor demonstrated a significant
increase in the LI of the liver metastatic foci.14 It is
this latter feature that provides a treatment window
for adjuvant therapy as a treatment modality after a
portion of the tumor burden is resected in a host with
disseminated tumor.
Tumor Immunogenicity
Human
There have been a variety of historical linkages of the
host-tumor immunologic response to NB, beginning
with the successful use of Coley toxin for treatment,26
the recognition that a significant surgical insult was
followed by spontaneous regression,27 and the publication by Everson and Cole that NB was the most
common human tumor to undergo spontaneous regression.28 Subsequently, subtherapeutic doses of radiation, putatively sparing the immune response, were
noted to be effective in NB control.29 Finally, the report
of nests of NB cells in the adrenal glands of autopsied
stillborn infants, at a frequency greater than that seen
clinically, further suggested a mechanism implicating
a host antitumor immune response.7
W: Cancer
Murine Neuroblastoma as a Disease Model/Ziegler et al.
FIGURE 3.
An in vitro aggregation kinetic assay of murine neuroblastoma cell lines, utilizing an initial single cell suspension of both C1300NB and TBJ-NB, demonstrates a greater dispersion characteristic for TBJNB. The Y-axis is an index of the extent of aggregation; Nt and N0 are
the number of aggregates (N) at incubation times t and 0, respectively.
This may correlate with its in vivo propensity for dissemination.
Hellstrom et al. first used in vitro assays in the
study of host antitumor immune response; and with
the colony inhibition assay, they found that lymphocytes harvested from tumor-bearing patients were able
to inhibit in vitro tumor growth.30,31 This was defined
as a tumor specific response subject to blocking by
serologic factors in NB patients, an inhibition which
was strengthened when both lymphocytes and sera
came from the same patient. The authors of these
studies further defined complement-dependent cytotoxic antibodies to NB, antibodies which themselves
were capable of neutralizing the serologic factor of
the blocking antibody. These data were subsequently
challenged because lymphocytes in control patients
were assigned the status of no reactivity to NB, when
in fact spontaneous anti-NB activity of lymphocytes
did occur in normal patients.
Subsequent investigations refined the component
parts of the antitumor immune response, including
the role of oncogenes32; oncofetal and neurofetal antigens33; cellular subsets, including NK cells and T-cell
subsets; and the components of humoral immunity.34
Lampson et al. then reported a critical observation,
which demonstrated that human NB cell lines weakly
express class I HLA-A, B, C, and B-2 microglobulin, an
expression needed to foster T-lymphocyte interaction
with NB tumor specific antigen.35 A modulation of this
expression by interferon was also demonstrated,36 and
others have suggested a further down-regulation of
/ 7b55$$1041
04-02-97 14:43:51
cana
1761
such expression by N-myc amplification.10 However,
the same investigators demonstrated a natural host
NK cell cytotoxic activity to NB and a lack of cytotoxic
T-lymphocyte activity.37 This NK activity has been
demonstrated in clinical patients with local NB; however, in contrast, such NK activity has been impaired
in patients with Stage IV metastatic NB, an effect potentially mediated by host monocytes.38 Such NK activity can be enhanced by both recombinant interferon-a and recombinant interleukin-2 in both healthy
and tumor-bearing children, showing an enhancement of potentially synergistic activity.38
Anti-NB T-cell activity has more recently been observed by analysis of the T-cell receptor repertoire of
tumor-infiltrating lymphocytes in human NB tumors.39 Not only are some tumor-infiltrating lymphocytes clonally expanded, but this enhanced expression
may be secondary to antigen or superantigen recognition, and it may afford a mechanism for tumor growth
control or even a mechanism for tumor regression.39
Antibodies to NB have proved useful for purging
autologous bone marrow of NB cells in preparation for
transplantation.40 Such antibodies would have further
diagnostic or therapeutic application if issues regarding receptor specificity and cross-reactivity with neural tissue and normal adrenal tissue were resolved.Monoclonal antibodies of murine origin have been raised
to a glycolipid antigen on human NB cells41,42 but not
on bone marrow cells.43 Additional murine monoclonal antibodies have been raised to cytoplasmic antigens,44 to human NB cell surface glycoproteins,45 and
specifically to the disialogangliosides GD2 and GD3.46
These latter antibodies have been shown in vitro to
effect significant tumor lysis by both complement-dependent and antibody-dependent antitumor activity.46,47 The addition of interferon-a has had a salutary
influence on NB cell killing.48 In vivo application of
antibody in diagnosis and therapy has relied on the
conjugation of the antibody with radioisotopes or
other antitumor agents. Such applications are potentially limited by the development of human antimouse
antibody; however, this response can be suppressed
by pretreatment with myeloablative chemotherapy.49
Antibody to the ganglioside GD2 antigen binds
with exquisite specificity in mediating either antibodydependent or complement-dependent cellular cytotoxicity,50 a cytotoxicity further enhanced by cytokines.51
Murine monoclonal antibodies have also been
raised to NB NCAM. Not only is NCAM uniformly expressed on NB cells, but it is also uniformly expressed
on human NK cells. However, NCAMs probably do not
mediate a role in the cytolytic interaction between NK
cells and NCAM positive tumor cells.52 L1, a member
W: Cancer
1762
CANCER May 1, 1997 / Volume 79 / Number 9
FIGURE 4. Northern blot analysis of N-myc, L1, and NCAM mRNA in murine neuroblastoma cell lines, C1300-NB (lane 1) and TBJ-NB (lane
2). (A) High expression of N-myc mRNA (2.9 Kb, closed arrow) was observed in TBJ NB. (B) L1 mRNA (6 Kb, closed arrow) expression was
much stronger in TBJ NB as well. (C) Both cell lines identically express neural cell adhesion molecule (NCAM) mRNA (2.9, 5.2, 6.9, and 7.1 Kb,
closed arrows).
of the NCAM family and an important factor in cellcell adhesion, has been demonstrated, along with
NCAM, to be expressed in a cell line from a patient
with advanced NB associated with N-myc amplification.53
Immunotherapy for human NB must overcome
the hurdle of a lack of a tumor specific antigen as well
as the failure of NB to express class I MHC antigen;
thus, the effectiveness of T-cell mediated cytotoxicity
is still limited. These issues have been addressed by
the use of immunotherapeutic agents, such as recombinant interferon (r-IFN)-a or -g, IL-2, LAK cells, or
tumor-infiltrating lymphocytes, alone or in combination. When r-IFN-g has been used in children with
extensive disease, an increased expression of class I
antigen has been demonstrated, but there has been
no demonstrated impact on patient outcome.54 The
clinical efficacy of IL-2, with and without LAK cells,
has been tested in advanced stage disease; and in combination with chemotherapy and autologous bone
marrow transplantation, a favorable response rate has
been observed.55,56,57
In a Phase II trial that used 3F8 mouse monoclonal
antibody to GD2, a tumor response was induced in
40% of patients with advanced NB.58 A Phase I trial of
14 G2a also demonstrated a response in refractory
Stage IV NB. Further therapy will take advantage of
antibody combined with cytokines to augment cytotoxicity59; and in recombinant therapy, human/mouse
chimeric antibody may be utilized to avoid the limitations induced by human antimouse antibody.60
/ 7b55$$1041
04-02-97 14:43:51
cana
Murine
The immunobiology of murine NB has been studied
extensively.1,15 In murine NB, both basal and inducible
NK activity exists, and depletion of the cell population
augments NB growth and decreases animal survival.61,62 Treatment with rIFN-g or r-IL-2 prolongs the
tumor latency period, decreases tumor weight, and
enhances tumor cell in vitro lysis by NK cells.62,63 These
effects are eliminated by NK cell functional blockade.
Such NK antitumor activities seem to be less well developed for the TBJ-NB clone.
Cytotoxic T lymphocytes have also been shown to
exert some influence on C1300-NB, and conflicting reports suggest that such anti-NB cytotoxicity is enhanced by ablation of suppressor cell activity.13,61 Significant transferable, antitumor, augmented spleen cell
activity was seen when adjuvant cyclophosphamide
was administered after subtotal resection of C1300NB.13 In another experiment, when cyclophosphamide
was administered 3 days after C1300-NB inoculation in
a subtherapeutic dose, presumably ablating suppressor
cells, no augmented antitumor cytotoxicity was demonstrated.61 A stronger cytotoxic lymphocyte anti-NB activity has been observed after suppressor cell ablation
during TBJ-NB growth.
These data are consistent with those of human
NB,36,37 in which up-regulation of class I antigen by rIFN can potentiate T-cell killing of NB. The data are
also consistent with the observation of increased NKtumor lysis and LAK-cell lysis when tumor was pretreated with r-IFN gamma.63,64 More recent reports
W: Cancer
Murine Neuroblastoma as a Disease Model/Ziegler et al.
have emphasized genetic tumor manipulation by
transfecting IFN-g producing gene into a NB cell line65
or cotransducing a neuro-2a clone of C1300-NB with
both B7-1 and an IFN-g gene.66 Class I MHC expression is up-regulated in each circumstance, and a CD8
positive T-cell response is effective in rejecting the
tumor. Similarly, actively infecting C1300-NB cells
with measles virus elicits a host cytotoxic T-lymphocyte response that lyses both infected and uninfected
NB cells in an H-2 restricted fashion.67 Additional studies of T-lymphocyte function have focused on the role
of surface accessory molecules essential to the antitumor response. Using a low major histocompatibility
antigen expressing neuro-2a mouse NB, tumor cells
were transduced to evaluate the role of B7-1 expression in tumorigenesis. The result was reduced tumorigenesis with improved animal survival, in part mediated by stimulation of CD8 positive T-cells.68 Finally,
in an experiment that examined the influence of local
IL-2 production on tumorigenesis and the immune
response against a low MHC-expressing NB, transduction of neuro-2a NB with a retroviral vector LIL-25N
showed that IL-2 reduced NB tumorigenesis.69 Furthermore, the response was primarily a CD8 positive
T-cell and not a NK or CD4 positive mediated T-cell
response.69
Immunoglobulins to murine NB have been developed and represent a highly specific immunoglobulinG antibody,70 which has been utilized effectively to
localize residual tumor.
The role of intercellular adhesion molecules
(ICAM) in influencing NB cell cytolysis and metastasis
has been reviewed. In an ICAM-1 transfected murine
NB line, ICAM expression was associated with decreased tumorigenesis with prolonged animal survival
but no alteration in metastatic spread.71 The alteration
in tumorigenesis may be related to a primary role in
cell-mediated lysis. The TBJ-NB, a highly metastatic
NB line, has previously been examined for both NCAM
and L1 expression; and in contrast to the nonmetastatic C1300-NB, L1 expression is enhanced for the TBJ
clone72,73 (Fig. 4). The roles of these factors in immunemediated antitumor activity is unknown, but a parallel
enhanced expression of N-myc was observed in the
same line.
The above data, which details the host-tumor immunologic response, by definition also outlines probable immunotherapeutic options in the murine NB
model. Additional forms of active immunotherapy in
the murine model have been reported with the use of
tumor ablation with either an electrocautery or a carbon dioxide laser. Both techniques of tumor ablation
are not only effective in local tumor control but also
may augment a systemic antitumor immune-based re-
/ 7b55$$1041
04-02-97 14:43:51
cana
1763
sponse.74,75 This may be similar to the active immunotherapy of operative tumor spillage first reported by
Koop et al.27
Tumor vaccines have been developed in two ways:
by treating C1300-NB cells with r-IFN-g, and by infecting murine NB cells with measles virus.64,67 In both
circumstances, the hosts have reacted with a sustained
immunity to both treated as well as untreated NB cells,
but whether the antitumor immune response is T-cell
mediated is less certain.
Cytokine therapy is outlined above; and in the
murine NB models, both r-IFN and r-IL-2 have been
effective for primary and metastatic NB by mechanisms that augment NK, LAK, and CD8 positive cytotoxic lymphocytes. These murine data are compatible
with and form a biologic basis for clinical immunotherapy trials that are currently being conducted.
A variety of adjuvant immunostimulants have
been tried in murine NB. BCG, inoculated into the
base of a residual C1300 NB after subtotal excision, has
resulted in tumor growth inhibition and even cures in
animals.1 A similar salutary antitumor effect was not
observed with r-IFN-g modified C1300 NB in combination with BCG, nor did Corynebacterium parvum or
levamisole in place of BCG produce any antitumor
activity.1
Restorative immunotherapy utilizing this nutritional repletion or the immunoactive amino acid arginine has been extensively studied in C1300-NB. Arginine supplementation in mice bearing C1300-NB has
retarded tumor growth, prolonged survival, and enhanced T-cell, NK cell, LAK, and macrophage antitumor cytotoxicity.62,76 Another form of such immunotherapy is the administration of adjuvant low dose cyclophosphamide after cytoreductive surgery in mice
bearing C1300-NB. This treatment selectively impaired
suppressor cell function; as a result, antitumor cytotoxic T-cells become more effective in tumor growth
control.13
Finally, adoptive immunotherapy, such as the
r-IL-2 plus LAK therapy being tested in human NB,
has not been tested in vivo in the murine NB model.
However, r-IL-2 induced LAK activity has been demonstrated in the murine system.14,63,64
CONCLUSIONS
NB remains an enigmatic tumor. This report has detailed the many behavioral and therapeutic similarities
that exist between human NB and the murine NB
model for human disease. Although there are important differences in histology as well as in certain
cell surface characteristics, the similarities in class I
antigen expression, adhesion molecules, host-antitumor activity, metastatic pattern, catecholamine me-
W: Cancer
1764
CANCER May 1, 1997 / Volume 79 / Number 9
tabolism, and maturational changes emphasize the
real value of further elucidating murine host-tumor
relationships. To date, investigators have been unable
to identify either the stage or the associated characteristics of a spontaneously regressing murine NB. With
the deciphering of the molecular basis for neurobiology and the availability of transgenic murine techniques, further elucidation of murine host-NB tumor
relationships should have a significant impact on our
understanding of the human NB tumor.
16.
17.
18.
19.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Ziegler MM, Naito H, McCarrick JW III, Topolian SL, Ricci
JL, Fox A, et al. C-1300 murine neuroblastoma: a suitable
animal mode of human disease. In: Brooks BF. Malignant
Tumors of Childhood. Austin: University of Texas Press,
1986:114–26.
Chatten J, Shimada H, Sather HN, Wong KY, Siegel SE, Hammond GD. Prognostic value of histopathology in advanced
neuroblastoma: a report from the Children’s Cancer Study
Group. Hum Pathol 1988;19:1187–98.
Joshi VV, Cantor AB, Altshuler G, Larkin EW, Neill JS, Shuster
JJ, et al. Age-linked prognostic categorization based on a
new histologic grading system of neuroblastomas: a clinicopathologic study of 211 cases from the Pediatric Oncology
Group. Cancer 1992;69:2197–211.
Hayes FA, Mauer AM. Cell kinetics and chemotherapy in
neuroblastoma. J Natl Cancer Inst 1976;57:697–9.
Fitzgibbon MC, Tormey WP. Paediatric reference ranges for
urinary catecholamines/metabolites and their reference in
neuroblastoma diagnosis. Ann Clin Biochem 1994;31:1–11.
Carlsen NL. How frequent is spontaneous remission of neuroblastomas? Implications for screening. Br J Cancer
1990;61:441–6.
Beckwith JB, Perrin EV. In situ neuroblastomas: a contribution to the natural history of neural crest tumors. Am J Pathol
1963;43:1089–104.
Squire R, Fowler CL, Brooks SP, Rich GA, Cooney DR. The
relationship of class I MHC antigen expression to stage IV–
S disease and survival in neuroblastoma. J Pediatr Surg
1990;25:381–6.
Knudson AG Jr., Meadows AT. Regression of neuroblastoma
IV–S: a genetic hypothesis. N Engl J Med 1980;302:1254–6.
Nakagawara A, Sasazuki T, Akiyama H, Kawakami K, Kuwano A, et al. N-myc oncogene and stage IV–S neuroblastoma: preliminary observations on ten cases.Cancer
1990;65:1960–7.
Kogner P, Barbany G, Dominici C, Castello MA, Raschella
G, Persson H. Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in
neuroblastoma with favorable prognosis. Cancer Res 1993;
53:2044–50.
Pritchard J, Wickman JA. Why does stage IV–S neuroblastoma regress spontaneously? Lancet 1994;344:869–70.
Naito H, Ziegler MM, Tsou KC. Rational selection of adjuvant
chemotherapy after cytoreduction surgery for murine neuroblastoma. Cancer Res 1985;45:3554–60.
Ishizu H, Arya G, Bove KE, Ziegler MM. Immune-mediated
regression of ‘metastatic’ neuroblastoma in the liver. J Pediatr Surg 1994;29:155–60.
Pons G, O’Dea RF, Mirkin BL. Biological characterization of
/ 7b55$$1041
04-02-97 14:43:51
cana
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
the C-1300 murine neuroblastoma: an in vivo neural crest
tumor model. Cancer Res 1982;42:3719–23.
Ruben GD, Ziegler MM. Influence of primary tumor site on
lymphocyte anti-tumor activity. J Pediatr Surg 1983;18:30–
3.
Choi SH, Lim TS, Hwant EH. Influence of primary tumor site
on host anti-tumor immunity. Yonsei Med J 1992;33:258–64.
Schengrund CL, Repman MA, Sheffler BA. Response of mature mice to challenge with neuroblastoma after inoculation
with neuroblastoma cells as neonates. Cancer Lett 1982;
17:229–35.
Sakamoto I, Kawakatsu H, Kidowaki T, Matumura T, Sugimoto T, Sawada T. Experimental study of the maternal effects on tumor immunity of infant mice with C-1300 mouse
neuroblastoma. J Pediatr Surg 1988;23:350–3.
Brodeur GM. Patterns and significance of genetic changes
in neuroblastomas. In: Pretlow TGJ, Pretlow TP. Biochemical
and molecular aspects of selected cancers. San Diego: Academic Press, 1991:251.
Nakagawara A, Arima-Nakagawara M, Scavarda NJ, Azar CG,
Cantor AB, Brodeur GM. Association between high levels of
expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 1993;328:847–54.
Castle VP, Heidelberger KP, Bromberg J, Ou X, Dole M, Nunez G. Expression of the apoptosis-suppressing protein bcl2, in neuroblastoma associated with unfavorable histology
and N-myc amplification. Am J Pathol 1993;143:1543–50.
Figarella-Branger DF, Durbee PL, Rougan GN. Differential
spectrum of expression of neural cell adhesion molecule
isoforms and L1 adhesion molecules on human neuroectodermal tumors. Cancer Res 1990;50:6364–70.
Kowitz A, Kadman G, Verschueren H, Remels L, DeBaetselier
PD, Hubbe M, et al. Expression of L1 cell adhesion molecule
is associated with lymphoma growth and metastasis. Clin
Exp Metastasis 1993;11:419–29.
Linnemann D, Raz A, Bock E. Differential expression of cell
adhesion molecules in variants of K1735 melanoma cells
differing in metastatic capacity. Int J Cancer 1989;43:709–
12.
Nauts HC. Immunotherapy of cancer: the pioneer work of
Coley. Giovinasso, Italy: International Symposium on Endotoxin, 1986.
Koop CE, Kiesewetter WB, Horn RC Jr. Neuroblastoma in
childhood: survival after major surgical insult to tumor. Surgery 1955;38:272–8.
Everson TC, Cole WH. Spontaneous regression of cancer.
Philadelphia: Saunders, 1966:88–163.
Koop CE. Abdominal tumors in infants and children. Arch
Dis Child 1960;35:1–16.
Hellstrom I, Hellstrom KE, Bill AH, Pierce GE, Yang JPS.
Studies on cellular immunity to human neuroblastoma cells.
Int J Cancer 1970;6:172–88.
Hellstrom KE, Hellstrom I. Immunity to neuroblastomas and
melanomas. Ann Res Med 1972;23:19–38.
Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong
KY, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J
Med 1985;313:1111–6.
Akeson R, Herschman H. Neural antigens of morphologically differentiated neuroblastoma cells. Nature 1974;
249:620–3.
Terman DS, Stewart I, Tovel A, Kirch D. Localization of neuroblastoma in vivo with tumor specific antibodies. Cancer
Res 1975;35:17616.
W: Cancer
Murine Neuroblastoma as a Disease Model/Ziegler et al.
35. Lampson LA, Fischer CA, Whelan JP. Striking paucity of
HLA-A, B, C, and B2 microglobulin on human neuroblastoma cell lines. J Immunol 1983;130:2471–8.
36. Lampson LA, Fischer CA. Weak HLA and beta2-microglobulin expression of neuronal cell lines can be modulated by
interferon. Proc Natl Acad Sci U S A 1984;81:6476–80.
37. Main EK, Lampson LA, Hart MK, Kornbluth J, Wilson DB.
Human neuroblastoma cell lines are susceptible to lysis by
natural killer cells but not by cytotoxic T lymphocytes. J
Immunol 1985;135:242–6.
38. Alvarado CS, Findley HW, Chan WC, Hnath RS, AbdelMageed A, Paris RC, et al. Natural killer cells in children with
malignant solid tumors: effect of recombinant interferon-2
and interleukin-2 on natural killer cell function against tumor cell lines. Cancer 1989;63:83–9.
39. Valteau D, Scott V, Carcelain G, Hartmann O, Excudier B,
Hercend T, et al. T-cell receptor repertoire in neuroblastoma
patients. Cancer Res 1996;56:362–9.
40. Seeger RC, Siegel SE, Sidell N. Neuroblastoma: clinical perspectives, monoclonal antibodies, and retinoic acid. Ann Int
Med 1982;97:873–84.
41. Cheung NK, Saarinen UM, Neely JE, Landmeier B, Donovan
D, Coccia PF. Monoclonal antibodies to a glycolipid antigen
on human neuroblastoma cells. Cancer Res 1985;45:2642–
9.
42. Saito M, Yu RK, Cheung NK. Ganglioside GD2 specificity of
monoclonal antibodies to human neuroblastoma cell. Biochem Biophys Res Comm 1985;127:1–7.
43. Frantz CN, Duerst RE, Ryan DH, Gelsomino NL, Constine
LS, Gregory PK. Anti-neuroblastoma monoclonal antibodies
which do not bind to bone marrow cells. Prog Clin Biol Res
1985;175:485–99.
44. Gross N, Beck D, Carrel S, Munoz M. Highly selective recognition of human neuroblastoma cells by mouse monoclonal
antibody to a cytoplasmic antigen. Cancer Res 1986;46:2988–
94.
45. Mujoo K, Spiro RC, Reisfeld RA. Characterization of a unique
glycoprotein antigen expressed on the surface of human
neuroblastoma cells. J Biol Chem 1986;261:10299–305.
46. Honsi KCJ, Jung G, Reisfeld RA. Lymphokine-activated killer
cells targeted by monoclonal antibodies to the disialogangliosides GD2 and GD3 specifically lyse human tumor cells of
neuroectodermal origin. Proc Natl Acad Sci U S A 1986;
83:7893–7.
47. Kawashima I, Tada N, Fujimori T, Tai T. Monoclonal antibodies to disialogangliosides: characterization of antibodymediated cytotoxicity against human melanoma and neuroblastoma cells in vitro. J Biochem 1990;108:109–15.
48. Mayer P, Handgretinger R, Bruchelt G, Schaber B, Rassner
G, Fierbeck G. Activation of cellular cytotoxicity and complement-mediated lysis of melanoma and neuroblastoma cells
in vitro by murine antiganglioside antibodies MB3.6 and
14.G2a. Melanoma Res 1994;4:101–6.
49. Cheung NK, Cheung IY, Carete A, Yeh SJ, Kushner B, Bonilla
MA, et al. Antibody response to murine anti-GD2 monoclonal antibodies: correlation with patient survival. Cancer
Res 1994;54:2228–33.
50. Cheung NK. Immunotherapy: neuroblastoma as a model.
Pediatr Clin North Am 1991;38:425–41.
51. Hank JA, Surfus J, Gan J, Chew TL, Hong R, Tans K, et al.
Treatment of neuroblastoma patients with antiganglioside
GD2 antibody plus interleukin-2 induces antibody-dependent cellular cytotoxicity against neuroblastoma detected in
vitro. J Immunol 1994;15:29–37.
/ 7b55$$1041
04-02-97 14:43:51
cana
1765
52. Lanier LL, Chang C, Azuma M, Ruitenberg JJ, Hemperly JJ,
Phillips JH. Molecular and functional analysis of human natural killer cell-associated neural cell adhesion molecule
(NCAM/CD56). J Immunol 1991;146:4421–6.
53. Melino G, Vernole P, Annicchiarico-Petruzzelli M, Stephanou A, Colantoni A, Knight RA, et al. An inducible cell
line (Natasha), from a neuroblastoma patient with circulating HRS-positive blasts, expressing neurohormones. Anticancer Res 1992;12:1199–206.
54. Evans A, Lampson L, Main E, Zier K, Ikegaki N, Tortaglione
M, et al. Effects of gamma interferon on the NK and tumor
cells of children with neuroblastoma. Proc AACR 1988;
29:416.
55. Ribeiro RC, Rill D, Roberson PK, Furman WL, Pratt CB, Brenner M, et al. Continuous infusion of interleukin-2 in children
with refractory malignancies. Cancer 1993;72:623–8.
56. Favrot MC, Michon J, Floret D, Cochat C, Negrier S, Mathiot
C, et al. Interleukin 2 immunotherapy in children with neuroblastoma after high-dose chemotherapy and autologous
bone marrow transplantation. Pediatr Hematol Oncol 1990;
7:275–84.
57. Negrier S, Michon J, Floret D, Bouffet E, Gentet JC, Philip I,
et al. Interleukin-2 and lymphokine-activated killer cells in
15 children with advanced metastatic neuroblastoma. J Clin
Oncol 1991;9:1363–70.
58. Cheung NK, Burch L, Kushner BH, Munn DH. Monoclonal
antibody 3F8 can effect durable remissions in neuroblastoma patients refractory to chemotherapy: a phase II
trial. In: Evans AE, D’Angio GJ, Knudson AG, Seeger RC.
Advances in neuroblastoma research. New York: Wiley-Liss,
Inc., 1991:395–400.
59. Handgretinger R, Baader P, Dopfer R, Klingebiel T, Reuland
P, Treuner J, et al. A phase I study of neuroblastoma with
the anti-ganglioside GD2 antibody 14.G2a. Cancer Immunol
Immunother 1992;35:199–204.
60. Yu AL, Gillies SD, Reisfeld RA. Phase I clinical trial of ch14.18
in patients with refractory neuroblastoma. Proc Am Soc Clin
Oncol 1991;10:318.
61. Choi SH, Reynolds JV, Ziegler MM. Systematic analysis of
the immunoregulation of murine neuroblastoma. J Pediatr
Surg 1989;24:15–20.
62. Reynolds JV, Shou J, Choi H, Sigal R, Ziegler MM, Daly JM.
The influence of natural killer cells in neuroblastoma. Arch
Surg 1989;124:235–8.
63. Sigal RK, Reynolds JV, Markman JF, Shou J, Evantosh E,
Ziegler MM, et al. Upregulation of MHC class I: effect on
growth and LAK sensitivity of neuroblastoma. Surg Forum
1988;39:527–75.
64. Sigal RK, Lieberman MD, Reynolds JV, Williams N, Ziegler
MM, Daly JM. Tumor immunization: improved results after
vaccine modified with recombinant interferon gamma. Arch
Surg 1990;25:308–12.
65. Watanabe Y, Kuribayashi K, Miyatake S, Nishihara K, Nakayama E, Taniyama T, et al. Exogenous expression of mouse
interferon gamma cDNA in mouse C1300 cells results in
reduced tumorigenicity by augmented anti-tumor immunity. Proc Natl Acad Sci U S A 1989;86:9456–60.
66. Katsanis E, Bausero MA, Panoskaltsis-Mortari A, Dancisak
BB, Xu Z, et al. Irradiation of singly and doubly transduced
murine neuroblastoma cells expressing B7-1 and producing
interferon-gamma reduces their capacity to induce systemic
immunity. Cancer Gene Ther 1996;3:75–82.
W: Cancer
1766
CANCER May 1, 1997 / Volume 79 / Number 9
67. Gopas J, Itzhaky D, Segev Y, Salzberg S, Trink B, Isakov N,
et al. Persistent measles virus infection enhances major histocompatibility complex class I expression and immunogenicity of murine neuroblastoma cells. Cancer Immunol Immunother 1992;34:313–20.
68. Katsanis E, Xu Z, Bausero MA, Dancisak BB, Gorden KB,
Davis G, et al. B7-1 expression decreases tumorigenicity and
induces partial systemic immunity to murine neuroblastoma deficient in major histocompatibility complex and
costimulatory molecules. Cancer Gene Ther 1995;2:39–46.
69. Katsanis E, Orchard PJ, Bausero MA, Garden KB, McIvor RS,
Blazar BR. Interleukin-2 gene transer into murine neuroblastoma decreases tumorigenicity and enhances systemic
immunity causing regression of preestablished retroperitoneal tumors. J Immunother Emphasis Tumor Immunol
1994;15:81–90.
70. Goldman A, Gordon I, Pritchard J, Kemshead J. A monoclonal antibody, UJ13A, used for radioimmunolocalization
of neuroblastoma in an animal model and patients. Prog
Exp Tumor Res 1985;29:85–92.
71. Katsanis E, Bausero MA, Xu H, Orchard PJ, Xu Z, McIvor RS,
/ 7b55$$1041
04-02-97 14:43:51
cana
72.
73.
74.
75.
76.
et al. Transfection of the mouse ICAM-1 gene into murine
neuroblastoma enhances susceptibility to lysis, reduces in
vivo tumorigenicity and decreases ICAM-2 dependent killing. Cancer Immunol Immunother 1994;38:135–41.
Nagabuchi E, Kunikane H, Krishan A, Arya G, Ziegler MM.
In vitro invasiveness in comparison with the expression of
MHC-1 antigen in murine neuroblastoma. Proc Am Assoc
Cancer Res 1994;35:62.
Nagabuchi E, Itoh K, Krishan A, Kunikane H, Ziegler MM.
Expression of the L1 molecule in highly metastatic murine
neuroblastoma. Proc Am Assoc Cancer Res 1995;36:62.
Ziegler MM, Vega A, Koop CE. Electrocoagulation-induced
immunity: an explanation for regression of neuroblastoma.
J Pediatr Surg 1980;15:34–7.
McCormack CJ, Naim JO, Rogers DW, Ziegler MM, Hinshaw
JR. Beneficial effects following carbon dioxide laser excision
on experimental neuroblastoma. J Pediatr Surg 1989;24:201–
3.
Reynolds JV, Daly JM, Zhang S, Evantash E, Shou J, Sigal R,
et al. Immunomodulatory mechanisms of arginine. Surgery
1988;104:142–51.
W: Cancer
Документ
Категория
Без категории
Просмотров
2
Размер файла
179 Кб
Теги
632
1/--страниц
Пожаловаться на содержимое документа