This paper was presented at the President's Cancer Panel
Conference on Avoidable Causes of Cancer held 7-8 April 1994 in Bethesda,
Maryland. Manuscript received: 9 March 1995; manuscript accepted: 24 March
1995.
This work is supported in part by a Junior Faculty Research
Award from the American Cancer Society and by a Clinical Epidemiology Fellowship
from Merck and the Society for Epidemiologic Research.
Address correspondence to Dr. Julie Parsonnet, Departments
of Medicine and Health Research and Policy, HRP Building, Room 225, Stanford
University School of Medicine, Stanford, CA 94305. Telephone: (415) 723-7274.
Fax: (415) 725-6951. E-mail:
ml.jxp@forsythe.stanford.edu
Abbreviations used: IPSID, immunoproliferative small intestinal
disease; MALT, mucosal associated lymphoid tissue: IARC International Agency
for Research on Cancer.
Introduction
A substantial number of bacterial pathogens have been putatively linked
to cancer. As early as 1772, Mycobacterium tuberculosis was thought
to cause malignancy (1). It was observed that bronchogenic carcinomas
frequently appeared in areas of pulmonary scarring, presumably from tuberculosis.
Persons with lung cancer also were noted to have active tuberculosis more
frequently than the general population. Like many hypotheses attributing
cancer to specific infectious agents, however, the tuberculosis-cancer theory
did not stand the test of time. Most bronchogenic carcinomas in persons
with tuberculosis do not occur at scar sites but elsewhere in the lung.
Furthermore, observed scars at tumor sites now appear to be the result of
the malignancy rather than the cause. Any link between active tuberculosis
and malignancy is currently ascribed to reactivation of infection in immunocompromised
cancer patients rather than to a cause-and-effect relationship between infection
and neoplasm (2-4).
Despite this early misstep, bacterial theories for carcinogenesis continue
to be promulgated (5). Now, however, rather than directly attributing
cancer to specific organisms, attention has focused on nonspecific mechanisms
of carcinogenesis. Two such mechanisms are induction of inflammation, and
production of mutagenic compounds by bacterial metabolism. The first mechanism
is best exemplified by Helicobacter pylori infection and gastric
cancer. Colon cancer provides a model for the second of these mechanisms.
Yet a third mechanism, that for lymphomas, has yet to be credibly modeled.
Bacteria, Inflammation, and Cancer: the Helicobacter
pylori Model
Infections have been nonspecifically tied to malignancy through their
ability to cause chronic inflammation. Among the chronic inflammatory processes
linked to cancer are parasitic infections [e.g., Schistosoma haematobium
and Opisthorchis viverrini (6,7)] and viruses [hepatitis
B (8)]. In general, these infections cause cancer in direct proportion
to their chronicity; the longer the inflammatory process persists, the more
likely malignancy is to develop (7,8). Among bacterial inflammatory
processes, chronic osteomyelitis was the first to be convincingly associated
with cancer in humans. Constant irritation of a draining sinus tract by
inflammatory exudates of the underlying bone predisposes the host to carcinoma
of the skin, regardless of the specific bacterial pathogen involved (9).
Fortunately, in the era of antibiotics chronic osteomyelitis contributes
a vanishingly small number of cases to the cancer registry. A similar mechanism
has been proposed for bladder cancer in persons with recurrent or persistent
cystitis (10,11).
Currently, a popular model for bacterial carcinogenesis is that of Helicobacter
pylori infection and gastric adenocarcinoma. H. pylori is a Gram-negative
rod that lives in a neutral pH niche between the mucus layer of the stomach
and the gastric epithelium. Although H. pylori can be found lining
the mucus layer adjacent to ectopic gastric tissue (e.g., in Meckel's diverticula),
it is never found remote from gastric epithelium and does not invade tissue;
it neither enters epithelial cells nor penetrates the basement membrane.
Despite this lack of invasion, H. pylori infection is invariably
associated with inflammation (12,13). Once established, H. pylori
infection and its associated inflammation are thought to last for decades
if not a lifetime (14). At least 50% of the world's population harbors
the organism (14).
Recently, H. pylori was declared by the International Agency for
Research on Cancer (IARC) to be a Group 1 carcinogen, a definite cause of
human cancer (7). Support for this decision came principally from
pathologic studies of the natural history of gastric adenocarcinoma and
epidemiologic studies statistically linking H. pylori to malignancy.
Chronic superficial gastritis has long been thought to be a precursor
lesion to gastric adenocarcinoma (15,16). Even in the absence of
more advanced preneoplastic lesions, superficial gastritis increases cancer
risk 2-fold (17). In approximately 3 to 5% of persons per year, superficial
gastritis progresses to chronic atrophic gastritis, a more advanced cancer
precursor lesion (18-20). With extensive atrophy, cancer risk increases
up to 9-fold (17). As atrophy worsens, patches of intestinal metaplasia
arise and the gastric epithelium transforms to either small or large bowel
morphology. Cancer ensues thereafter.
Since H. pylori causes the vast majority of superficial gastritis,
it can be deduced from the data above that H. pylori is a likely
risk factor for malignancy and increases cancer risk at least 2-fold. The
role of H. pylori in the development of chronic atrophic gastritis
and intestinal metaplasia is unclear. Atrophic gastritis and intestinal
metaplasia are inhospitable to H. pylori, and biopsies taken from
these areas yield no organisms. In spite of this, H. pylori often
is identified in nonatrophic locations of the same stomach (21).
Moreover, in most persons with atrophy or intestinal metaplasia, anti-H.
pylori IgG is found in serologic assays, suggesting smoldering infection
(22,23). In support of a causal role, one study has suggested that
cytotoxin-producing strains of H. pylori are more common in persons
with chronic atrophic gastritis than in persons with only superficial gastritis
without atrophy (24).
An animal system to confirm the H. pylori cancer model has yet
to be established. Thus, epidemiologic studies provide the strongest evidence
for the link between H. pylori and cancer. Correlations between H.
pylori prevalence and gastric cancer incidence reveal both geographic
and temporal parallels. In two of the largest ecologic studies, Forman et
al. found significant correlations between H. pylori seroprevalence
and gastric cancer rates among 49 rural Chinese counties and 17 nations
worldwide (25,26). Other investigators observed that the prevalence
of H. pylori and/or superficial gastritis has declined over time
concomitant with the decrease in gastric cancer incidence (27-29).
Smaller ecological studies yield less consistent results (23,30,31).
Similarly, while some case-control studies of H. pylori in gastric
cancer have shown significant associations between infection and malignancy
(32-35), others have not (36-40).
The most convincing data implicating H. pylori as a cause of cancer
are four nested case-control studies from Hawaii, California, Great Britain,
and Taiwan (41-44). In the first three studies (mean follow-up 13,
14, and 6 years, respectively), serologic evidence of H. pylori infection
increased risk of later developing gastric cancer between 2.8- and 6-fold
(41-43). The fourth nested case-control study also identified an
elevated risk of cancer (odds ratio=1.6), but the finding was not statistically
significant (44). This last study was hampered, however, by a small
number of cases (n=29) and short follow-up period (mean=3 years).
Overall, the association between H. pylori and cancer appeared to
be restricted to tumors distal to the gastric cardia (41,43).
A combined analysis of three nested case-control studies showed the strongest
association between infection and cancer (odds ratio=8.7) when the interval
between serum collection and cancer diagnosis was longer than 15 years (45).
When serum was drawn more proximate to the time cancer occurred, the relative
risk estimate was considerably lower (odds ratio=2.1). This has been observed
independently by other investigators (46) and suggests that antibody
titers, and perhaps the presence of infection itself, might diminish as
preneoplastic lesions progress toward cancer.
The epidemiologic and pathologic associations between H. pylori and
cancer would have little meaning were infection not a biologically plausible
cancer risk factor. H. pylori infection, like other infectious causes
of chronic inflammation, theoretically fits the role of a promoter in the
multistage model of carcinogenesis (6). Promoters select for clonal
expansion of cells either by causing alteration in increasing proliferation
and gene expression or by causing changes in terminal cell differentiation
(47,48). H. pylori infection causes increased cell proliferation
(49,50). Eradication of H. pylori decreases cell proliferation,
probably because of decreased inflammation rather than loss of the organism
itself (50-52). Although H. pylori-related hyperproliferation
is not yet understood, possible causes are direct damage to mucosal cells
by H. pylori-related factors (i.e., ammonia), trophic effects of
increased gastrin production, or indirect damage to the epithelium by the
inflammatory response (49,53-57). Cell proliferation in turn increases
risk for DNA replication error and predisposes mucosal cells to transformation
by dietary or endogenous mutagens (58,59).
Other elements of inflammation also can be seen as tumor-promoting processes
(48,58). Inflammatory cells increase conversion of nitrates to nitrites,
enhancing the likelihood of N-nitrosamine formation (6). This
may explain the epidemiologic observation that in some populations high
dietary nitrates increase gastric cancer risk (60). Moreover, activated
macrophages produce nitrite, nitrate, and nitrosating agents (61).
When macrophages are cultured with appropriate amines, N-nitroso
compounds are formed. Free radicals produced by the inflammatory response,
e.g., O- and superoxide, alter the structure and function of
lipids, proteins, and DNA causing changes in cell metabolism and gene expression.
Excess production of reactive oxygen species has been noted in human mucosal
tissue infected with H. pylori (62,63). Thus, without being
directly genotoxic, H. pylori can contribute to the development of
uncontrolled cell growth.
Because H. pylori is curable with a short course of antibiotics,
it is tantalizing to speculate that treatment of infection or creation of
a vaccine could prevent gastric cancer. Unfortunately, studies proving this
almost certainly will be difficult or impossible to perform. Very large
cohorts would be needed with many years of follow-up. Intermediate markers
for cancer risk are easier to evaluate, and the effects of therapy on advanced
precursor lesions are currently being studied. Pending these results, a
preliminary cost-effectiveness analysis suggests that even if treatment
prevents only 20% of infection-related cancers, antibiotic therapy could
be a reasonable approach to disease prevention in high risk groups such
as Japanese-Americans and African-Americans (64).
Colon Cancer and Bacterial Colonization of the Intestine
For obvious reasons, research into the etiology of sporadic colon cancer
has focused on dietary influences (65). After decades of study, several
trends are evident: fats are consistently risk factors for colon cancer
and fiber is consistently protective. Mechanisms for these associations
are not yet clear. One widely held theory, however, is that risks attributable
to foods are mediated by bacterial actions in the intestine.
The intestine harbors an enormous variety of bacterial flora, with colonization
becoming more dense progressing from pylorus to distal colon. In the proximal
duodenum, few organisms survive. In the colon, on the other hand, it is
estimated that 1014 organisms of hundreds of different species
(the vast majority anaerobes) vie for space and nutrients. Despite the wide
diversity of resident organisms, differences in composition of gut flora
within human populations have been difficult to substantiate, even in persons
with very different diets (66).
Bacteria are thought to have several indirect carcinogenic actions in
the gut. First, they deconjugate and reduce bile acids. While most bile
acids are absorbed in the small intestine, a small percent will pass into
the colon. In vitro, it has been shown that bacterial species within
the colon can deconjugate the 7
-hydroxyl groups from
bile acids to produce cytotoxic 7-dehydroxylating bile
acids (deoxycholate and lithocholate) (67). These compounds are reported
to promote cell proliferation (68) and growth of adenomas (69).
This in turn enhances carcinogenesis by exogenous or endogenous mutagens.
Thus, copious secretion of bile acids following fatty meals would increase
risk of colon cancer in persons with high fat diets.
Bacteria are also thought to activate exogenous mutagen precursors. Examples
observed in vitro and in vivo are: hydrolysis of rutin to
quercetin (a mutagenic aromatic amine), hydrolysis of cycasin to methylazoxymethanol
(70), and hydrolysis of glucuronide-conjugated polycyclic hydrocarbons
to their unconjugated, mutagenic forms (71). Fecapentaenes, potent
mutagens synthesized by Bacteroides species, are also found in relatively
high concentrations in human feces, although their relationship to cancer
is unproven (72-74). Furthermore, bacteria ferment polysaccharides
and glycoproteins to volatile fatty acids. These may increase distal colon
cell proliferation by altering membrane structure, although, again, in
vivo support for this is lacking (75,76).
Because of the many species of bacteria in the gut (a considerable portion
of which remain unidentified), focusing on any one organism as a cause of
cancer is a daunting task. It remains possible, however, that specific bacterial
species play more direct roles in colon carcinogenesis. In murine models,
Citrobacter freundii causes attaching and effacing lesions of the
large intestine similar to those caused by enteropathogenic Escherichia
coli in humans (77). Animals infected with Citrobacter freundii
develop colonic hyperplasia and when exposed to exogenous mutagens,
progress more rapidly to malignancy than uninfected animals (78,79).
In humans, efforts have been made to similarly identify specific organisms
that cause proliferation and/or malignancy. For example, several cross-sectional
studies indicate that certain Clostridium species are more common
in colon cancer patients than in other subjects, although a causal relationship
remains unproven (80,81). In light of the Citrobacter freundii
model, however, it is conceivable that specific bacteria may induce
the optimal proliferative environment for mutagens to induce their damage.
Unlike the H. pylori model outlined above, there is little hope
that anti-bacterial strategies will play a role in colon cancer prevention.
Normal flora are a fundamental component of the human gastrointestinal tract.
Since no specific species of organism has been targeted as the colon cancer
culprit, no antimicrobial therapy or vaccine can be explored. Until a specific
organism is pinpointed, cancer prevention strategies can only focus on diet
as it influences bacterial pathogenesis.
Lymphomas
Circumstantially, bacteria appear to be involved in pathogenesis of two
types of lymphomas: gastric lymphomas and immunoproliferative small intestinal
disease (IPSID). Although the stomach is not a lymphoid organ, gastric lymphoma
is the most common extranodal lymphoma. Approximately 20 to 30% of these
tumors arise from mucosal-associated lymphoid tissue (MALT). MALT consists
of organized lymphoid follicles in mucosal areas of nonlymphoid organs such
as the GI tract and thyroid and salivary glands. Recently, Isaacson showed
that MALT can be the nidus for B-cell neoplasms called MALT lymphomas (82).
These low-grade malignancies are characterized by specific histologic features:
nonneoplastic lymphoid follicles, centrocytelike cells, lymphoepithelial
lesions, and plasma cell differentiation.
One line of research currently favors H. pylori infection as a
causal factor in both MALT and non-MALT gastric lymphomas. Several facts
favor this hypothesis. First, gastric MALT is extraordinarily common in
patients with H. pylori infection. One pathologist has suggested
that all infected subjects will have MALT if the pathologist diligently
looks for it (83). H. pylori is also common in subjects with
MALT lymphomas (84). Gastric MALT lymphoma cells proliferate when
cultured in the presence of T-cells and H. pylori antigens (85).
In a mouse model of H. felis, lymphoid follicle formation was followed
by MALT-like tumors after several years of sustained infection (86).
More remarkable still, gastric MALT and MALT lymphomas remit coincident
with cure of H. pylori infection, although a nonspecific response
to antibiotics cannot be ruled out (87,88). The only prospective
epidemiologic study done in humans, however, found that H. pylori infection
increased risk for all gastric lymphomas not just MALT lymphomas (odds ratio=6.3)
(89). This suggests that infection is driving the proliferation of
MALT cells and the progression of MALT to both MALT and non-MALT lymphomas.
Another hypothesis is that MALT lymphoma reflects an aberrant autoimmune
response to chronic infection (82,90).
The second bacterium-related lymphoma, IPSID, is an unusual malignancy
that occurs predominantly in young adults of lower socioeconomic regions
of the southern and eastern Mediterranean region. Commonly known as Mediterranean
lymphoma, IPSID is a MALT-type lymphoma that is almost invariably associated
with excessive production of a heavy chains (91). Like gastric MALT
lymphoma, IPSID responds to antibiotic therapy. When treated in the early
stage, up to 40% of tumors will completely regress with antibiotic treatment
(typically tetracycline) (91-93). The precise reason for these remissions
remains unclear. One widely held theory is that IPSID succeeds unremitting
bacterial stimulation of lymphocytes (93). In particular, recurrent
diarrheal disease beginning in infancy has been implicated as a stimulus
for uncontrolled lymphoproliferation. Bacterial overgrowth of the small
bowel is evident in some cases, although no specific bacterium appears to
be more common than in controls (93).
Because nonnodal lymphomas are rare, these diseases are difficult to
study. Furthermore, the variable pathologic classifications of lymphomas
makes consistency among investigators difficult. Even the distinction between
lymphoma and lymphoproliferation often is problematic. Thus, the true nature
of the relationship between bacteria and lymphomas remains obscure. Whether
the bacterial disease model can be applied to other extranodal or non-MALT
lymphomas is unknown.
Conclusions
One of the most intimate relationships of man is that which he has with
his own microbial flora. While most exposures in life are transient, the
contact we have with these microorganisms is constant and unremitting. This
symbiotic relationship is taken for granted or, more commonly still, thought
to be beneficial. Even the term normal flora suggests benignity. Yet it
is naive to assume that our continuous interaction with microbial flora
is immaterial to our long-term health. As new infectious causes of malignancy
continue to be uncovered, it is increasingly apparent that dissection of
the complex interplay between man and microbial flora is essential to understanding
the pathogenesis of many malignancies.
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