炎症与肿瘤的相关性研究概述
Yonago Acta medica 2014;57:65–72 Review Article: Special Contribution Inflammation-Related Carcinogenesis: Current Findings in Epidemiological Trends, Causes and Mechanisms
Futoshi Okada*?
*Division of Pathological Biochemistry, Department of Biomedical Sciences, School of Life Science, Tottori University Faculty of Medi-cine, Yonago 683-8503, Japan and ?Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan
ABSTRACT
Inflammation is a definite cancer-causing factor as re-vealed by cumulative basic, clinical and epidemiologi-cal studies. It is mostly induced by infectious agents. For instance, infection with papillomaviruses associates with anogenital cancers, especially cervical cancers; Helicobacter pylori infection of the stomach tends to increase the risk of stomach cancer; chronic hepatitis B & C viruses and fluke infections of the liver increase liver cancers; autoimmune diseases, e.g., inflammatory bowel diseases, associate with development of colorec-tal cancer, and aerial irritants (foreign bodies) such as asbestos or fine particulate matter (PM2.5) in outdoor air increase malignant pleural mesotheliomas or lung cancers. These are typical examples of inflammation-related carcinogenesis. It is apparent that the pathogens to induce inflammatory reactions in specific organs are not related to each other. However, the underlying pathogenesis in common is to induce and/or sustain inflammation. In this article, I would like to review the up-to-date findings of epidemiological trends, causes and mechanisms of inflammation-related carcinogen-esis.
Key words carcinogenesis; inflammation; mouse model
Cancer is classified as noncommunicable disease as cardiovascular diseases, chronic respiratory diseases and diabetes are. They are mostly chronic diseases of long duration and generally slow development. While they are assumed to develop from aging, urbanization, and unhealthy lifestyles, it has also become known that Corresponding author: Futoshi Okada, PhD
fuokada@med.tottori-u.ac.jp
Received 2014 May 29
Accepted 2014 May 29
Abbreviations: COPD, chronic obstructive pulmonary disease; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HERV-K, human endogenous retrovirus type K; HIV-1, human immunodeficiency virus; HPV, human papillomavirus; HTLV-1, human T-cell lymphotropic virus type 1; JCV, JC virus; KSHV, Kaposi sarcoma herpes virus; MCV, molluscum contagiosum virus; Mn-SOD, manganese-SOD; PM, particulate matter; QR cells, regressive cells; ROS, reactive oxygen species; SOD, superoxide dismutase.low-grade chronic inflammation, which is characterized by increased systemic levels of inflammatory cytokines and inflammation-responsible protein (C-reactive protein), is one of the underlying key mechanisms.1 Indeed, estimated 20–25% of all cases of cancer worldwide are associated with inflammation induced by microbial infection. Extended life span, dietary factors and physical inactivity; mutation and replicating errors; environmental pollutants including aerial irritants and tobacco; and radiation and ultraviolet are linked to car-cinogenesis today. Nevertheless, persistent inflamma-tion resulting from infection or autoimmunity is most evidently associated with the onset of carcinogenesis.2 The relation of inflammation to cancer was first postulated by Galenus around 1,800 years ago.3 He pro-posed that tumors arose from inflammatory tissue injury and that the tumors and the tissue were pathophysi-ologically similar.3 Centuries later in 1863, Virchow confirmed Galenus’s hypothesis from his own observa-tion that lymphoreticular infiltrates, namely inflamma-tion, preceded tumor development.4 This possible link between injurious inflammation and cancer was also pointed out later by Dvorak who revealed that tumor tis-sues resembled wound tissues because both tissues were composed of similar stromal cell types such as infiltrat-ed inflammatory cells and angiogenesis-related cells; the only difference he pointed out was that tumor tissues did not terminate (heal) but wound healed finally.5
Undoubtedly antitumor immunity exists, since par-ticular kinds of tumors are formed only in patients with iatrogenic immunosuppression such as melanoma and nonmelanoma skin cancer in organ transplant recipi-ents, lymphoma in patients with lymphoproliferative disorders, or Kaposi’s sarcoma in patients with immu-nosuppressive infection such as with HIV. However, the generality of the arising tumors are sarcomas and hematologic malignancies, and carcinomas that account for the majority of human carcinogenesis seldom occur in the immunosuppressed patients. Discussions have suggested that antitumor immunity might work only in the very initial phase of carcinogenesis or work against particular kinds of tumorigenesis only. An opinion has even suggested that antitumor immune effector cells may act as stimulant to carcinogenesis. In the 1970s,
F. Okada
Prehn proposed that immune effector cells contributed to carcinogenesis, and named the phenomenon as “im-munostimulation theory of tumor development.”6 From the achievements of our predecessors carried out over the two millennia, we have solid evidence that an inflammatory environment can be an essential risk for induction of various types of carcinomas. Recent results add that inflammation-related carcinogenesis is influenced not only by individual age and sex, but also by regional/geographical and economical development statuses of country. I review the current evidence on the inflammation-related carcinogenesis and propose pos-sibly effective preventive/therapeutic strategies based on our elucidation of inflammation mechanism obtained by using our animal model.
EPIDEMIOLOGICAL TREND OF INFLAMMATION-RELATED CARCINOGENESIS
It is obvious that incidences of inflammation-related cancers are not in a homogenous background but in a complex one influenced by individual age, sex, living region, era and also development status of country as revealed in the recent epidemiological studies.
Chronologically the incidences of inflammation-related carcinogenesis also differ. In the United States, cancer epidemiologists estimated in the 1980’s that around 75% of cancers was due to three cancer-causing factors: daily diet, smoking and infection/inflammation.7 Currently the three major factors are thought to account for 43% of cancer causes.8 Involvement of inflammation in the total cancer incidences was reduced from 10% to 5%.9
There are geographical differences in the incidences of inflammation-caused cancers. Namely, contribution of inflammation to carcinogenesis greatly varies among continentals, countries, and even in the regions within a country. Figure 1 shows the ratios of infection/inflam-mation to all the cancer death causes: around 25% in sub-Saharan Africa, around 6% in Europe.8 In general, the proportions were higher in less developed countries (23%) than in more developed countries (7%) including North America and Europe (10). Lowest ratios were in Australia and New Zealand (3%), while other parts of Oceania showed higher ratios (18%). In contrast to the highest ratio in sub-Saharan Africa (25%), the rates are lower in North Africa and west Asia (13%). In east Asia, the rates are high: Japan (20%), China (26%), South Ko-rea (21%) and India (21%).10 Considering the high ratios, east Asia including Japan is still a developing region.
The geographical and regional differences in the incidences of inflammation-related carcinogenesis may arise from the economic standing or development status of each country; i.e., the standard of life, the levels of medical care and education, etc. will make up the char-acteristic of a country as a whole. In addition, prevalence of the four main infectious agents, HPV, HBV, HCV and Helicobacter pylori, differs among economically and geographically different regions. Relative contribution of HPV to cancer burden is similar in both developed and developing countries. However, that of Helicobacter py-lori is larger in developed countries, and those of HBV and HCV are larger in developing countries.10
There were estimated 14.1 million new cancer cases and 8.2 million cancer deaths globally in 2012; of the cancer deaths, about 65% (5.3 million) was in less de-veloped countries.11 Since the infectious agents account for as much as 20% of all of the cancer-causing factors, we could estimate that around 2.8 million new cancer cases and around 1.7 million deaths would be attribut-able to infection/inflammation. It is greatly apprehended that new cancer cases/deaths due to inflammation would increase rapidly in the developing countries within a few decades as a result of upcoming population growth.12 Although the total number of cancer cases due to inflammation is much the same between men and wom-en,10 there are some sex- and age-dependent differences in particular cancers: stomach cancer, liver cancer, oro-pharynx cancer, bladder cancer, Hodgkin’s lymphoma and Kaposi’s sarcoma are much higher in men than in women.10 And it is obvious that around 30% of inflam-mation-related cancers (cervical cancer, Hodgkin’s lym-phoma and Kaposi’s sarcoma) are in individuals younger than 50 years, compared to other inflammation-related cancers which develop mostly in those older that 50 years.10
CAUSES OF INFLAMMATION-RELATED CAR-CINOGENESIS
Infections induced by certain viruses, bacteria, parasites or foreign bodies and following prolonged inflammation have been identified as grave risk factors for develop-ment of specific cancers. Table 1 shows infectious agents classified as definitely carcinogenic to humans by the International Agency for Research on Cancer and those classified as presumably carcinogenic according to ex-perimental and clinical reports.10
MECHANISMS OF INFLAMMATION-RELATED CARCINOGENESIS DETERMINED IN AN EX-PERIMENTAL MODEL
Close association between inflammation and carcino-genesis has been indicated by clinical and epidemio-logical studies; however, there is hardly a solid animal model in which carcinogenesis by inflammation can
Inflammation-related carcinogenesis
Fig. 1. Causes of cancer differ from country to country. Europe, excluding east Europe; Africa, representing sub-Saharan countries only.
be evidently observed. To demonstrate the direct link between inflammation and carcinogenesis, our group established several animal models in which tumorigenic conversion or acceleration of carcinogenic processes of rat, mouse or human cells occurs in the presence of inflammation. In this section, I summarize the results of our thorough investigation using one of our mouse models and introduce our elucidation of the mechanism responsible for inflammation-related carcinogenesis and theoretical preventive strategies.
To establish the experimental model for carcino genesis especially focusing on acquisition of tumori genicity in vivo, we had to choose cells which were immortalized, non-tumorigenic, and non-metastatic but would grow in vitro, bearing the concept of xenogenization in mind. “Xenogenization of tumor cells” is the term meaning immunologically spontaneous regression of tumor cells which have been infected with xenogeneic viruses,13 transfected with the genes coding allogeneic antigen,14 or exposed to mutagenic chemicals,15 after injected into normal syngeneic host.
We obtained regressive clonal QR cells from clonal tumorigenic fibrosarcoma cells, BMT-11 cl-9, by expos-ing them in vitro to a mutagen/carcinogen (quercetin); they were non-tumorigenic and non-metastatic in nor-mal syngeneic C57BL/6 mice, and we termed the phe-nomenon as “chemical xenogenization of tumor cells.”15 By using the regressive QR cells, we can easily detect internal/external factors which are closely associated with carcinogenic process through the conversion of their regressive phenotypes into lethally tumorigenic ones, after injecting QR cells previously treated in vitro with a candidate material, or co-implanting QR cells with it, into mice. As shown in the Fig. 2A, QR cells did not develop tumor after (2 × 105 cells) subcutaneously injected into mice.15 Since QR cells grew progressively in immunosuppressed hosts, we determined that their regression was mediated by host immunity.16 Infiltrated inflammatory cells are necessary and sufficient to accelerate carcinogenesis
A serendipitous finding was that the regressive QR cells were spontaneously converted to grow lethal after im-planted into a pre-inserted piece of hemostasis gelatin sponge which induced foreign-body-reactive inflam-mation at the implantation site (Fig. 2B).17 Significance of the foreign-body-induced inflammation on carcino-genesis was confirmed by using other materials such as plastic plate. In this case, too, various phenotypic altera-tions occurred following QR cell conversion.18 All of the arising tumors were found to have acquired tumorigenic and metastatic phenotypes, and the acquired malignant phenotypes remained stable as far as examined for de-cades at least under cultivation in vitro. An increase in prostaglandin E2 production followed the acquisition of tumor-forming ability, which particularly suppressed immunological host-defense against tumors. Angio-
genesis, motility and invasion capacities of tumorigenic
F. Okada
Table 1. Definitely and presumably carcinogenic agents in inflammation-related carcinogenesis in human
Sites of inflammation- Causes of inflammation/pathological condition
related carcinogenesis Definitely carcinogenic Presumably carcinogenic
Oral cavity HPV type 16 HPV type 18, gingivitis, lichen planus, leukoplakia
Salivary gland Sialadentis
Tongue HPV, caries, gingivitis
Tonsils HPV type 16
Nasopharynx EBV
Pharynx HPV type 16 Asbestos
Oropharynx HPV
Larynx Asbestos HPV type 16
Thyroid Chronic lymphocytic thyroiditis, Hashimoto’s thyroiditis Esophagus Gastric reflux, esophagitis, Burrett’s esophagus,
Neisseria mucosa, Neisseria sicca, Neisseria subflava
Lung Asbestos, coal gasification, outdoor Asthma, bronchitis, COPD, interstitial pneumonia, sarcoidosis,
air pollution,* tobacco smoke silicosis, tuberculosis, Chlamydia pneumoniae
Lung mesothelium Asbestos Silicosis
Breast HERV-K, inflammatory breast cancer
Stomach Helicobacter pylori Asbestos, EBV, chronic atrophic gastritis
Liver HBV, HCV, Clonorchis sinensis, HDV, HIV type 1, Schistosoma japonicum, hemochromatosis
Opisthorchis viverrini alpha-1-anti-trypsin deficiency, alcohol
Bile duct Clonorchis sinensis, Bile acids-associated cholangitis
Opisthorchis viverrini
Gall bladder Gall bladder stone-associated cholecystitis, Salmonella typhimurium Pancreas Chronic pancreatitis, alcoholism-associated pancreatitis,
hereditary pancreatitis, primary sclerosing cholangitis, alcohol Colon & Rectum Bile acids-associated coloproctitis, inflammatory bowel diseases,
cytomegalovirus, EBV, HPV, JCV, Bacteroides,
Clostridiumsepticum, Escherichia coli, Helicobacter pylori,
Streptococcus bovis, Streptococcus gallolyticus,
Schistosoma japonicum, asbestos
Bladder Schistosoma haematobium C ystitis, urinary catheter-associated cystitis
Anus HIV type 1, HPV type 16 HPV types 18, 33, anal fistula
Prostate Prostatitis, proliferative inflammatory atrophy, gonorrhea, chlamydia,
mumps virus, Trichomonas vaginalis
Ovary Asbestos Pelvic inflammatory disease
Uterine cervix HPV types 16, 18, 31, 33, 35, 39, HPV types 26, 53, 66, 67, 68, 70, 73, 82;
45, 51, 52, 56, 58, 59; HIV type 1 herpes simplex virus
Endometrium Endometriosis
Penis HPV type 16 HIV type 1, HPV type 18
Vulva HPV type 16 HIV type 1, HPV types 18, 33; lichen sclerosis
Vagina HPV type 16 HIV type 1
Skin UV-associated skin inflammation Chronic osteomyelitis, HIV type 1, HPV types 5, 8; MCV Melanoma UV-associated skin inflammation
Non-melanomatous
skin cancer Cutaneous HPV types
Central nerve JCV
Endothelium
(Kaposi’s sarcoma) HIV type 1, KSHV HIV-2
Vasculature Bortonella
Hodgkin’s lymphoma EBV, HIV type 1
Lymphoma EBV, HCV, HIV type 1, HIV type 2, Hashimoto’s thyroiditis, Sj?gren’s syndrome,
HTL V-1, KSHV childhood celiac disease, HBV, HTL V-1
Orbital lymphoma Chlamydia psittaci
Thyroid lymphoma Hashimoto’s thyroiditis
Lymphoma in the
pleural cavity Pyothorax-associated lymphoma
MALT lymphoma Helicobacter pylori
Small-bowel lymphoma Campylobacter jejuni
Continued on the following page
Inflammation-related carcinogenesis
cells converted from QR cells were also augmented in parallel with their malignant potential.18 Histologically, we observed emergence of abundant microvilli on the surface of the tumorigenic cells, a common phenomenon observed in other malignant tumor cell lines of rodent and human.19
We also determined several gene alterations through the inflammation-mediated conversion in this model (Fig. 3). The level of thymosin beta4 gene, which is known to be an actin-regulating protein and function for angiogenesis and wound healing, was elevated in all of the arising tumor cells. From the results of sense and an-tisense cDNA transfection experiments, we revealed that thymosin beta4 gene was responsible for tumor form-ing and/or metastasis through regulating cell motility.20 The expression of E1AF, a member of the ets oncogenic transcription factor, was found high in the arising tumor lines.21 E1AF regulates tumor cell motility and invasive activities through induction of membrane-type 1-matrix metalloproteinase (MT-1-MMP) which converts the la-tent form of matrix metalloproteinase-2 (MMP-2) into active form.21 Thus E1AF makes tumor cells invasive.21 We used foreign bodies to induce inflammation at the implanted site locally, which was to demonstrate direct association between inflammation and carcino-genesis in vivo. Evidence for the effects of inflammatory cells on carcinogenesis was also demonstrated by the following three experiments: i) By histological examina-tion, we found that neutrophils predominantly infiltrated into the inserted gelatin sponge in the very early phase.22 One of the features of using gelatin sponge is that it is possible to collect the infiltrated inflammatory cells by treating the sponge with collagenase (Fig. 4). It was clear that inflammation definitely contributed to the conver-sion of QR cells, since we found that the inflamed cells separated from the sponge could alter QR cells into le-thally tumorigenic ones in the experiment of mixing the both two kinds of cells and injecting them in mice (Fig. 2C).22 ii) To confirm the role of infiltrated neutrophils in inflammation, we eliminated neutrophils by administer-ing anti-neutrophil antibody (RB6). As a result, nearly all the arising tumors in the mice, non-treated or treated with control IgG, acquired malignant phenotypes. On the other hand, in RB6 antibody-administered mice, arising tumors did not acquire malignant phenotypes
Fig. 2. A mouse model of inflammation-related carcinogenesis. Regressive cells (QR) spontaneously regress in syngeneic normal mice after subcutaneous injection (A ). Tumorigenic conversion was observed in QR cells injected into subcutaneously pre-inserted gelatin sponge (B ). Tumorigenic conversion was also observed in QR cells which were mixed with gelatin-sponge-infiltrated inflammatory cells and injected in mice (C ). The model was also utilized to screen candidate drugs to prevent inflammation-related carcinogenesis (D ).
Adult T-cell leukemia ATL (HTL V-1)T-cell lymphoma EBV Burkitt’s lymphoma EBV B-cell lymphoma EBV Primary effusion lymphoma
KSHV
ATL, adult T-cell leukemia; COPD, chronic obstructive pulmonary disease; DLBC, diffuse large B-cell lymphoma; EBV , Epstein-Barr virus; HBV , hepatitis B virus; HCV , hepatitis C virus; HDV , hepatitis D virus; HERV-K, human endogenous retrovirus type K; HIV-1, human immunodeficiency virus; HPV , human papillomavirus; HTL V-1, human T-cell lymphotropic virus type 1; JCV , JC virus; KSHV , Kaposi sarcoma herpes virus; MALT, mucosa-associated lymphoid tissue; MCV , molluscum contagiosum virus.*Outdoor air pollutions with PM 10, PM 2.5, NO 2, SO 2 and O 3?PM 2.5.
Table 1–Continued Sites of inflammation- Causes of inflammation/pathological condition related carcinogenesis
Definitely carcinogenic
Presumably carcinogenic
F. Okada
(Fig. 2D).22 iii) We further confirmed the results in integrin-beta-2 knockout mice (C57BL/6J Itgb2tm1Bay equivalent to CD18-deficient). Integrin-beta-2 is the key adhesion molecule for the migration of neutrophils into an inflammatory region. Neutrophil infiltration into gelatin sponge was abolished and acquisition of tumori-genic phenotypes was suppressed in the integrin-beta-2 knockout mice.22
These findings show that neutrophils are one of the main components of inflammation-associated tumor de-velopment and progression. Interestingly, the capability of neutrophils to accelerate tumor cell malignancy varies depending on their activation phase, which we suggest from the finding that circulating or bone marrow neutro-phils do not convert regressive cells into malignant ones but infiltrated (activated) neutrophils do.22
Fig. 3. Alteration of key molecules through foreign-body-induced carcinogenesis in mice. A diagram of stepwise molecular alterations in QR cells associated with acquisition of malignant phenotypes, accelerated by inflammation.
Fig. 4. Advantages of using gelatin sponge for investigating inflammation-related carcinogenesi. There are advantages in using gelatin sponge for analyzing the inflammation-related carcinogenesis since sponge-infiltrated inflammatory cells can be collected by brief collagenase treatment. Then we can quantify inflammation by counting the number of infiltrated cells. Moreover, by using the infiltrated cells, we are able to analyze the inflammation by biological, molecular genetical, and cytological methods.
ROS produced by infiltrated inflammatory cells are the major cause for carcinogenesis
We assumed that reactive oxygen species (ROS) would be key molecules that stimulate carcinogenic process since ROS act on both initiation and promotion of can-cer. To determine the direct contribution of ROS to the carcinogenesis in our model, we used gp91phox gene-knockout mice. Bactericidal function of neutrophils brings about generation of superoxide anions by forming NADPH oxidase complex (gp22phox , gp40phox , gp47phox , gp67phox , gp91phox and Rac1/Rac2) from interaction with cytochrome b 558. The frequency of tumor development from the QR cells co-implanted with gelatin sponge was decreased in the gp91phox–/– mice.23 To determine wheth-er phagocyte-derived ROS were actually involved in tumor development, we isolated phagocytes from wild-type mice and transferred them into gp91phox–/–
mice.
Inflammation-related carcinogenesis
As a result, wild-type-derived phagocytes increased
the frequencies of tumor development. In contrast, the
phagocytes obtained from gp91phox gene-knockout mice
did not have such activity.23 Moreover, administration
of aminoguanidine, a broad inhibitor for inducible nitric
oxide synthase, partially but significantly suppressed
conversion in the model;24 thus we concluded that nitric
oxide (NO) was also involved in the process. These re-
sults show that ROS and NO, derived from foreign-body-
induced inflammatory cells, are an intrinsic factor in the
conversion of regressive cells to more malignant ones. Attempts to prevent inflammation-related carcino-genesis
When we determined the cause of inflammation-related
carcinogenesis, it appeared that the carcinogenesis
would be theoretically preventable: ROS are one of
the most crucial genotoxic mediators to accelerate the
carcinogenic process; then their antagonists, namely an-
tioxidative enzymes or antioxidants, will be effective to
prevent the process (Fig. 2D).
Accordingly, we tried to induce an antioxidative
enzyme, superoxide dismutase (SOD), at the inflamma-
tory site, hopefully by administration of orally active
SOD, in our model. We used a newly developed SOD,
named oxykine; as a result, the incidence of tumor for-
mation was significantly decreased due to induction of
manganese-SOD (Mn-SOD) in the inflamed region,
compared to the one under control vehicle treatment.25 It
should be noted that Mn-SOD was induced secondarily
to activation of host intestinal immunity instead of the
drug’s direct action to the inflamed site. Thus Mn-SOD
was induced at the inflamed site and the inflammation-
related carcinogenesis was suppressed. Based on these,
rationales for effective prevention of inflammation-
related carcinogenesis will be either by suppressing ROS
production of inflammatory cells or by blocking infiltra-
tion of inflammatory cells into the inflamed site. CONCLUSION & PERSPECTIVE Inflammation, especially chronic one, is the definite
cause for tumor development and progression, and it is
well referred to as “inflammation-related carcinogen-
esis”. The pathogens that cause various types of inflam-
mation-related carcinogenesis are obviously unrelated,
whereas the essential pathological feature in common
is continuous inflammation: initially infiltration of ac-
tivated phagocytes/lymphocytes and then stimulated
reaction of stroma composed mainly of fibroblasts and
angiogenesis-related cells. It is assumed that continuous
generation of ROS and NO by these infiltrated inflam-
matory cells is likely to injure normal cells. This could, in turn, cause compensatory cell proliferation, which will help accumulation of DNA damages/gene muta-tions and effectively incorporate internal/external car-cinogenic factors into the growth of stimulated normal cells. Apart from those, it has recently been revealed that inflammatory environments accelerate epigenetic alterations and the alterations could cause inflammation-related carcinogenesis.26 All these events accompanying inflammation are essential to carcinogenesis. In this sense, we may understand that an inflammatory envi-ronment is a niche for carcinogenesis.
Intriguingly, we noticed that all the chronic inflam-mation and dysregulated immunity do not always lead to carcinogenesis; for instance, some of the chronic inflam-matory diseases are not linked to cancer risk, and some are even leading to tumor regression. For instance, rheu-matoid arthritis is not linked to cancer risk even though the inflammatory regions in rheumatoid arthritis patients show mutations of tumor suppressor genes at similar frequencies to those in the digestive tract tumors aris-ing from chronic inflammatory reaction. Another thing to be noted here is that parasite (helminth, Trichuris suis) could diminish inflammatory response, and now its effects on inflammatory bowel diseases are under investigation. We may be able to determine the nature of inflammation which accelerates carcinogenesis by com-paring the typical two types of inflammation, i.e., pro-carcinogenic and anti-/unrelated-carcinogenic ones.
In our mouse model, inflammation induced by gela-tin sponge insertion causes acute-phase inflammation, which will not become chronic since the sponge is ab-sorbed spontaneously in the body. The actual inflamma-tion leading to carcinogenesis is mostly chronic; possibly there is some link between acute-phase inflammation and chronic inflammatory diseases. A few techniques are available to pursue researches of this aspect: Apheresis technology has made it possible to eliminate granulo-cytes and monocytes specifically from the patients with ulcerative colitis. By meta-analysis study, those patients with intensive granulocytes and monocytes adsorption make the higher rate of shift to clinical remission.27 It is important to find out whether there are some types of regulatory inflammatory cells in the early phase of in-flammation that may maintain and prolong inflammation. We have not fully elucidated the mechanisms of inflam-mation: how chronic inflammation is induced, activated, maintained and resolved; whether chronic inflammation is triggered by preexisting acute inflammation or it devel-ops independently. We should now move on to identify key regulators for induction/maintenance of chronic in-flammatory reaction that closely link to carcinogenesis, among which acute-phase inflammatory cells may be.
F. Okada
Acknowledgments: I thank Ms Masako Yanome for her help in English revision of this manuscript.
The author declares no conflict of interest.
REFERENCES
1 Mathur N, Pedersen BK. Exercise as a mean to control
low-grade systemic inflammation. Mediators Inflamm.
2008;2008:109502. PMID: 19148295.
2 Loomis D, G rosse Y, Lauby-Secretan B, El G hissassi F,
Bouvard V, Benbrahim-Tallaa L, et al. The carcinogenic-ity of outdoor air pollution. Lancet Oncol. 2013;14:1262-3.
doi:10.1016/S1470-2045(13)70487-X.
3 Trinchieri G. Cancer and inflammation: an old intuition
with rapidly evolving new concepts. Annu Rev Immunol.
2012;30:677-706. PMID: 22224761.
4 Balkwill F, Mantovani A. Inflammation and cancer: back to
Virchow? Lancet. 2001;357:539-45. PMID: 11229684.
5 Dvorak HF. Tumors: wounds that do not heal. Similarities
between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650-9. PMID: 3537791.
6 Prehn RT, Lappé MA. An immunostimulation theory of
tumor development. Transplant Rev. 1971;7:26-54. PMID: 4947774.
7 Doll R, Peto R. The causes of cancer: quantitative estimates
of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66:1191-308. PMID: 7017215.
8 G lobal action against cancer. Updated version [Internet].
Geneva: World Health Organization and International Union Against Cancer; c2005 [cited 2014 May 28]. p. 12. Available from: http://www.who.int/cancer/media/en/GlobalActionCan-cerEnglfull.pdf.
9 Kobayashi H. “One step” for cancer prevention. Asian Pac J
Cancer Prev. 2006;7:672-8. PMID: 17250451.
10 de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman
D, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol.
2012;13:607-15. PMID: 22575588.
11 GLOBOCAN 2012: Estimated Cancer Incidence, Mortality
and Prevalence Worldwide in 2012 [Internet]. Lyon: Interna-tional Agency for Research on Cancer; c2014 [cited 2014 May 28]. Available from: http://globocan.iarc.fr/Pages/fact_sheets_ cancer.aspx.
12 Thun MJ, DeLancey JO, Center MM, Jemal A, Ward EM.
The global burden of cancer: priorities for prevention. Carci-nogenesis. 2010;31:100-10. PMID:19934210.
13 Kobayashi H, Sendo F, Shirai T, Kaji H, Kodama T. Modifica-
tion in growth of transplantable rat tumors exposed to Friend virus. J Natl Cancer Inst. 1969;42:413-9. PMID: 5777490.
14 Itaya T, Yamagiwa S, Okada F, Oikawa T, Kuzumaki N,
Takeichi N, et al. Xenogenization of a mouse lung carci-noma (3LL) by transfection with an allogeneic class I major histocompatibility complex gene (H-2Ld). Cancer Res.
1987;47:3136-40. PMID: 3107804.
15 Ishikawa M, Okada F, Hamada J, Hosokawa M, Kobayashi H.
Changes in the tumorigenic and metastatic properties of tu-
mor cells treated with quercetin or 5-azacytidine. Int J Cancer.
1987;39:338-42. PMID: 2434441.
16 Okada F, Hosokawa M, Hasegawa J, Ishikawa M, Chiba I,
Nakamura Y, et al. Regression mechanisms of mouse fibro-sarcoma cells after in vitro exposure to quercetin: diminution of tumorigenicity with a corresponding decrease in the pro-duction of prostaglandin E2. Cancer Immunol Immunother.
1990;31:358-64. PMID: 2386981.
17 Okada F, Hosokawa M, Hamada JI, Hasegawa J, Kato M,
Mizutani M, et al. Malignant progression of a mouse fibrosar-coma by host cells reactive to a foreign body (gelatin sponge).
Br J Cancer. 1992;66:635-9. PMID: 1419599.
18 Okada F. Inflammation and free radicals in tumor develop-
ment and progression. Redox Rep. 2002;7:357-68. PMID: 12625943.
19 Ren J, Hamada J, Okada F, Takeichi N, Morikawa K,
Hosokawa M, et al. Correlation between the presence of mi-crovilli and the growth or metastatic potential of tumor cells.
Jpn J Cancer Res. 1990;81:920-6. PMID: 1977729.
20 Kobayashi T, Okada F, Fujii N, Tomita N, Ito S, Tazawa H, et
al. Thymosin-beta4 regulates motility and metastasis of ma-lignant mouse fibrosarcoma cells. Am J Pathol. 2002;160:869-
82. PMID: 11891186.
21 Habelhah H, Okada F, Kobayashi M, Nakai K, Choi S,
Hamada J, et al. Increased E1AF expression in mouse fibrosar-coma promotes metastasis through induction of MT1-MMP expression. Oncogene. 1999;18:1771-6. PMID: 10208438.
22 Tazawa H, Okada F, Kobayashi T, Tada M, Mori Y, Une Y,
et al. Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells: implication of inflammation-associated carcinogenesis and tumor progression. Am J Pathol. 2003;163:2221-32. PMID: 14633597.
23 Okada F, Kobayashi M, Tanaka H, Kobayashi T, Tazawa H,
Iuchi Y, et al. The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells. Am J Pathol.
2006;169:294-302. PMID: 16816381.
24 Okada F, Tazawa H, Kobayashi T, Kobayashi M, Hosokawa
M. Involvement of reactive nitrogen oxides for acquisition of metastatic properties of benign tumors in a model of inflam-mation-based tumor progression. Nitric Oxide. 2006;14:122-9.
PMID: 16125421.
25 Okada F, Shionoya H, Kobayashi M, Kobayashi T, Tazawa H,
Onuma K, et al. Prevention of inflammation-mediated acqui-sition of metastatic properties of benign mouse fibrosarcoma cells by administration of an orally available superoxide dis-mutase. Br J Cancer. 2006;94:854-62. PMID: 16508635.
26 Niwa T, Toyoda T, Tsukamoto T, Mori A, Tatematsu M,
Ushijima T. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent. Cancer Prev Res. 2013;6:263-70. PMID: 23559452.
27 Yoshino T, Nakase H, Minami N, Yamada S, Matsuura
M, Yazumi S, et al. Efficacy and safety of granulocyte and monocyte adsorption apheresis for ulcerative colitis: a meta-analysis. Dig Liver Dis. 2014;46:219-26. PMID: 24268950.
炎症在肿瘤发生发展中的作用
加强炎症在肿瘤发病发展中作用的研究 2014-05-15 09:41来源：中华内科杂志作者：林三仁 加强炎症在肿瘤发生发展中作用的研究许多慢性炎症，包括感染性和非感染性（或特发性） 炎症可以导致肿瘤。目前公认的宫颈炎与宫颈癌、EB病毒感染引起的炎症与鼻咽癌等。消化系统的许多炎症亦与肿瘤的发相关（表1）。炎症作为肿瘤发生发展的诱发因素，引起人 们越来越多的关注。尽管炎症在肿瘤的发生发展全过程的各个阶段的作用仍未完全阐明，但本领域的许多研究工作仍取得了重要的进展。炎症如何诱发肿瘤以及如何通过这些途径进行干预是当前肿瘤研究领域的重要科学问题。 表1 主要的消化系统肿瘤相关性炎症和相应肿瘤 注：Hp:幽门螺杆菌；MALT.黏膜相关淋巴组织
一、炎症导致肿瘤的机制 1．炎症与肿瘤起始：急性炎症往往是自限性的，而持续的慢性炎症是肿瘤干细胞转化为肿瘤的始动和持续促进因素。持续的或低强度的炎症刺激使靶组织处于长期或过度反应而反复 修复时，炎症表现为"非可控性"。肿瘤的发生过程中，肿瘤干细胞、基质细胞和炎性细胞等形成了复杂的调控网络，涉及到基因、非编码RNA、蛋白质和代谢小分子等众多"节点"，并形成相互影响的"互联网"。在肿瘤起始中，核转录因子NF-KB和转录激活因子3（STAT3）路径最为重要。 通过这些路径，可以释放促炎因子和重要的介质，它们对肿瘤增殖和维持炎症同样重要。其中NF-KB的活化具有抑制凋亡、加速细胞周期进程、促血管生成和转移的作用；STArI3路径是调控和参与多种肿瘤的信号转导通路，包括调控抗凋亡基因和细胞周期控制基因。2.炎症与肿瘤逃避免疫监视并增殖：肿瘤的存活与效应性T细胞和体液免疫反应的抑制有关。免疫系统不能产生足够的抗肿瘤效应的原因是由于：肿瘤细胞未分化的特性，和它对免疫系统有直接抑制作用并逃避免疫监视。调节性T细胞(Tregs)具有免疫抑制功能，在肿瘤组织中聚集，在炎症反应中，这些细胞也被树突状细胞募集和激活。 骨髓来源的抑制性细胞(MDSCs)亦属于促炎细胞，它被炎症反应激活，并向特定部位聚集， 促进血管形成，同时它也具有免疫抑制作用。因此，肿瘤相关性炎症通过产生促炎和抗炎信号，导致肿瘤生长并逃避免疫监视。 3．炎症与肿瘤进展及转移："种子和土壤"学说认为，肿瘤"种子"能在肿瘤微环境(TME)"土壤"中存活并转移，依赖于各种因子与肿瘤细胞的相互作用。TME由癌细胞和多种基质细胞、细胞因子、趋化因子等组成。其中基质细胞包括成纤维细胞、免疫细胞、内皮细胞、MDSCs等；细胞因子包括TNF、血管内皮生长因子(VEGF)、IL-1等；趋化因子包括CXCL12、CCL27、CCl21等。 这些细胞和因子产生并存在于肿瘤相关性炎症中，可以促进肿瘤的生长、血管形成、侵犯和 转移。肿瘤本身可以通过旁分泌的促炎因子（IL一1B、IL-6、TNFa）和自分泌细胞因子促进自身表达趋化因子（包括cxc趋化因子家族）受体。肿瘤进展依赖于肿瘤相关性巨噬
炎症因子与肿瘤指标的联合检测在原发性肝癌中的表达及相关性研究
炎症因子与肿瘤指标的联合检测在原发性肝癌中的表达及相关性研 究 目的：观察炎症因子联合肿瘤指标在原发性肝癌患者中的应用及相关性。方法：取2014年3月-2016年6月医院收治的原发性肝癌患者100例，设为观察组。取同期入院健康体检者50例，设为对照组。两组入院后均抽取5 ml静脉血，采用全自动生化分析仪测定其ALT、AST水平，采用酶联免疫吸附试验检测IL-2、IL-6水平，采用化学免疫发光法测定甲胎蛋白，分析炎症因子与肿瘤指标的联合检测在原发性肝癌患者中的应用及相关性。结果：观察组AST、ALT及AFP水平高于对照组，差异有统计学意义（P＜0.05）；对照组IL-2水平高于AFP阳性及AFP阴性者，差异有统计学意义（P＜0.05）；观察组100例肝癌患者中50例AFP阳性，50例AFP阴性。AFP阳性患者IL-2水平低于AFP阴性者，差异有统计学意义（P＜0.05）；AFP阳性患者IL-6水平，高于AFP阴性者，差异有统计学意义（P＜0.05）。结论：原发性肝癌患者中对于甲胎蛋白阳性者检测IL-2、IL-6水平效果理想，能为临床诊断、治疗提供依据和参考。 标签：炎症因子；肿瘤指标；乙肝；肝癌；相关性；化学免疫发光法；酶联免疫吸附试验 原发性肝癌是临床上流行最高的十种恶性肿瘤之一，临床可以分为胆管细胞型肝癌和肝细胞癌，具有发病率高、致死率高、治愈率低等特点[1]。目前，临床上对于原发性肝癌发病机制尚不完全知晓，多数患者由于乙型肝炎引起，且患者发病早期缺乏特异性症状，导致临床死亡率较高，影响患者健康[2]。目前，临床上对于原发性肝癌尚缺乏理想的诊断方法，单一的检测指标已经不能满足每一位患者诊断需要，导致临床指标联合测定显得至关重要。文献[3]报道显示：炎症因子联合肿瘤指标在原发性肝癌患者诊断中得到应用，该方法能帮助患者确诊，为临床诊治提供依据和参考，但是该结论尚未得到进一步证实。为了探讨炎症因子联合肿瘤指标在原发性肝癌患者中的应用及相关性，选取2014年3月-2016年6月医院收治的原发性肝癌患者100例，现报道如下。 1 资料与方法 1.1 一般资料 选取2014年3月-2016年6月医院收治的原发性肝癌患者100例，设为观察组。其中，男58例，女42例，年龄46～69岁，平均（52.54±9.85）岁。纳入标准：（1）符合2001年9月中国抗癌协会肝癌专业委员会第八届肝癌学术会议制定的“原发性肝癌的临床诊断与分期标准”[4]；（2）患者入院后未进行手术治疗。（3）本课题均经过医院伦理委员会批准同意，自愿签署知情同意书。排除标准：（1）排除不符合原发性肝癌临床诊断标准者；（2）排除合并有影响效应指标观测、判断其他生理或病理者；（3）排除合并传染性疾病及意识不清或存在精神障碍者；（4）排除健康人及无肝癌症状HBV携带者。取同期入院健康体检者50
肿瘤与炎症的关系
肿瘤发生、发展与炎症的关系 班级：2015级研究生学号20151051018 姓名：季科炎症与肿瘤的发生、发展具有相关性，它们通过内源性及外源性两条通路相互联系。炎症调节因子和效应细胞是肿瘤组织局部微环境的重要组成，它们在炎症与肿瘤相互关系中起着重要作用。 炎症与肿瘤相互关系的研究始于19世纪，研究表明，慢性炎性病灶常继发肿瘤发生，而肿瘤组织活检样本中存在炎症细胞。炎症与肿瘤之间的联系包括两个通路：外源性通路，由增加肿瘤风险的炎症诱导（如炎症性肠道疾病）；内源性通路，由可以引起炎症和肿瘤生成的基因改变所致（如致癌基因）。 1、外源性通路：流行病学研究证实，约25%的肿瘤由炎症发展而来。炎症可以是由微生物感染引起，也可以由非炎症性物理或化学性刺激引起。在胃肠道，幽门螺杆菌感染是腺癌和黏膜相关淋巴组织淋巴瘤的主要原因。在胆管，华支睾吸虫感染引起的慢性炎症浸润可以导致胆管癌。乙型和丙型肝炎病毒感染引起的慢性肝炎患者易患肝癌，居全球肿瘤死亡率第三位。非感染引起的慢性炎症也与癌变相关，食管炎、食管腺上皮化生、慢性胰腺炎可以增加食管癌、胰腺癌的发病风险。临床研究发现 ,溃疡性结肠炎与结肠癌、骨盆或卵巢炎症与卵巢癌、持续性细菌性感染或非感染性刺激引起的慢性前列腺炎与前列腺癌之间可存在相关性。所以，越来越多的证据支持慢性炎症与肿瘤发生之间存在相关性。 炎症微环境有直接的致突变作用，其中的白细胞生成大量活性氧和活性氮，可以产生诱变剂，如过氧化亚硝酸盐，与DNA反应导致增殖的上皮细胞和基底细胞发生突变。巨噬细胞和T 淋巴细胞可以释放TNF-α和巨噬细胞游走抑制因子，加速DNA损伤。另外，炎症通过直接或间接的作用参与了肿瘤血管新生和肿瘤细胞生长、侵袭和转移。 2、内源性通路：研究发现，炎症细胞和调节因子存在于大多数肿瘤的微环境中，也存在于没有炎症的流行病学基础的病例。人们猜想，在这些病例中引起肿瘤形成的基因改变是否导致了炎症微环境的形成。 在人类肿瘤中, RAS家族成员是最易发生突变的显性基因，而 RAS-RAF信号通路中激活的致癌成分又诱导了有促肿瘤作用的炎症化学趋化因子和细胞因子。MYC是在多种人肿瘤中过表达的转录因子，该基因的表达失常启动和维持着肿瘤表型的主要方面，除了有促细胞增殖作用,还影响了细胞外微环境的重塑，炎症细胞和调节因子在此过程中起了重要作用。在小鼠 MYC依赖的胰岛β细胞癌，血管新生首先由MYC诱导的炎症因子IL-1β引发。MYC激活了几个趋化因子的转录 ,它们对肥大细胞有募集作用。肥大细胞驱动了血管新生，在这种情况下，它们维持着新生血管的形成和肿瘤的生长。 虽然很多实验和临床结果都显示炎症有促肿瘤作用，但是也有结果并不支持这个结论。例如，很多显著的慢性炎症反应如牛皮癣与皮肤癌没有关系。而且，在某些肿瘤或者某些肿瘤亚型,炎症细胞与预后良好有关(如肠道肿瘤中的噬酸细胞，在乳腺癌的一个亚型和胰腺癌中的TAMs)。这些观察可能反应炎症细胞不仅破坏正常组织细胞，而且也破坏肿瘤细胞。例如，虽然在多数情况下，巨噬细胞起促肿瘤作用，但适当激活时，巨噬细胞能杀伤肿瘤细胞，并引发以作用于血管壁为中心的肿瘤破坏性炎症反应。 自然免疫反应可以促发抗肿瘤的保护性反应。早在19世纪末即有研究者观察到有些肿瘤患者的肿瘤病灶有严重术后感染时，机体产生自发的、持续的肿瘤抑制作用。 综上所述，炎症与肿瘤之间存在相关性，它们通过内源性与外源性通路相联系，促进了肿瘤微环境的形成。炎症调节因子在炎症与肿瘤相互关系中起着重要作用,
肿瘤的发生_发展及治疗与炎症的关系_吉登波
C h i n e s e J o u r n a l o f N e w D r u g s 2010,19(17) 中国新药杂志[基金项目] 国家“重大新药创制”科技重大专项(2009Z X 09301-010)[作者简介] 吉登波,女,博士后,主要从事基于炎症相关性肿瘤的药物研究。联系电话:(010)82801161,E -m a i l :j i d e n g b o @b j m u .e d u .c n 。[通讯作者] 崔景荣,女,博士生导师,教授,主要从事肿瘤药理学研究。联系电话:(010)82802467,E -m a i l :j r c u i @b j m u .e d u .c n 。 ·综述· 肿瘤的发生、发展及治疗与炎症的关系 吉登波,崔景荣 (北京大学药学院天然药物及仿生药物国家重点实验室,北京100191) [摘要] 炎症与肿瘤的发生、发展具有相关性,它们通过内源性及外源性两条通路相互联系。炎症调 节因子和效应细胞是肿瘤组织局部微环境的重要组成,它们在炎症与肿瘤相互关系中起着重要作用。肿瘤微环境中的炎症有多种促肿瘤作用,可以促进恶性细胞的增殖和存活,促血管新生和转移,削弱机体的获得性免疫反应,改变机体对激素和化疗药物的反应。肿瘤相关性炎症的通路的揭示,可以为进一步改进肿瘤诊断和治疗提供新的靶分子。理想的靶向于肿瘤相关性炎症的药物可以转化促肿瘤炎症浸润,阻止炎症细胞移行到肿瘤灶,将促肿瘤微环境调整为抑制肿瘤的微环境,增强特异的获得性免疫反应,抑制肿瘤生长、存活和转移播散。 [关键词] 肿瘤;炎症;肿瘤相关性炎症[中图分类号]R 730.23 [文献标志码]A [文章编号]1003-3734(2010)17-1551-05 R e l a t i o n s h i p b e t w e e nt h e i n i t i a t i o n ,d e v e l o p m e n t a n d t h e r a p y o f t u m o r a n di n f l a m m a t i o n J I D e n g -b o ,C U I J i n g -r o n g (S t a t e K e y L a b o r a t o r y o f N a t u r a l a n d B i o m i m e t i c D r u g s ,S c h o o l o f P h a r m a c e u t i c a l S c i e n c e s , P e k i n g U n i v e r s i t y ,B e i j i n g 100191,C h i n a ) [A b s t r a c t ] I n f l a m m a t o r y d i s e a s e s a r e a s s o c i a t e d w i t ht h e i n i t i a t i o n a n d d e v e l o p m e n t o f c a n c e r s .T h e y a r e l i n k e d b y i n t r i n s i c a n d e x t r i n s i c p a t h w a y s .I n f l a m m a t i o n r e g u l a t i n g f a c t o r s a n d e f f e c t o r c e l l s a r e i m p o r t a n t c o m p o -n e n t s o f m i c r o e n v i r o n m e n t i n t u m o r t i s s u e ,w h i c hh a v e i m p o r t a n t r o l e i n t h e c o n n e c t i o n b e t w e e n t h e i n f l a m m a t i o n a n d t u m o r .I n f l a m m a t i o n i n t h e t u m o r m i c r o e n v i r o n m e n t h a s m a n y t u m o r p r o m o t i n g e f f e c t s s u c ha s e n h a n c i n g t h e p r o l i f e r a t i o n a n d s u r v i v a l o f t u m o r c e l l s ,i n c r e a s i n g a n g i o g e n e s i s a n dm e t a s t a s i s ,a l l e v i a t i n g a d a p t i v e i m m u n e r e -s p o n s e ,c h a n g i n g r e a c t i o n s t o h o r m o n e s a n d c h e m o t h e r a p e u t i c d r u g s .T o r e v e a l t h e p a t h w a y a b o u t t u m o r -r e l a t e d i n -f l a m m a t i o n w i l l g i v e n e wt a r g e t s w h i c h c a n i m p r o v e t h e d i a g n o s i s a n d t h e r a p y .A n t i c i p a n t d r u g s t h a t t a r g e t c a n c e r -r e l a t e d i n f l a m m a t i o n c o u l d t r a n s f o r ma t u m o r -p r o m o t i n g i n f l a m m a t o r y i n f i l t r a t e ,p r e v e n t i n f l a m m a t o r y c e l l s f r o mm i -g r a t i n g t o t h e t u m o r s i t e ,a d j u s t a t u m o r -p r o m o t i n g m i c r o e n v i r o n m e n t t o b e c o m e a t u m o r -i n h i b i t i n g m i c r o e n v i r o n -m e n t ,e n h a n c e t u m o r -s p e c i f i c a d a p t i v e i m m u n e r e s p o n s e s a n d i n h i b i t t h e t u m o r p r o l i f e r a t i o n ,s u r v i v a l a n d m e t a s t a t -i c s p r e a d . [K e y w o r d s ] t u m o r ;i n f l a m m a t i o n ;t u m o r -r e l a t e d i n f l a m m a t i o n 炎症与肿瘤相互关系的研究始于19世纪。研究发现慢性炎症病灶常继发肿瘤发生,而肿瘤组织活检样本中存在炎症细胞。流行病学研究证实, 25%的肿瘤由炎症发展而来,炎症与肿瘤的发生具有相关性[1] 。与此相一致的是,用非类固醇类抗炎 药物可以降低某些肿瘤的发病率和死亡率[2] 。肿瘤相关性炎症的标志包括肿瘤组织中炎症细胞和炎症调节因子、与慢性炎症反应中相似的组织重塑和血管新生以及组织修复。一些与炎症相互关系还未确定的肿瘤中也可见这些炎症标志(如乳腺癌)。实际上,无论炎症细胞和调节因子是否促进
肿瘤核素诊断方法
肿瘤核素诊断方法 核医学概述 核医学是利用放射性核素(同位素)发射出的射线来诊断、治疗疾病的一门学科。肿瘤核医学是核医学的主要组成部分。肿瘤核医学包括核素诊断和核素治疗。 利用放射性核素实现脏器和病变显像的方法称作放射性核素显像，这种显像是一种独特的功能依赖性显像，可早期发现及诊断疾病，可同时显示多个脏器与组织的影像。因各个脏器和病变聚集各种放射性显像剂机理不同而选择不同的显像剂。 肿瘤核医学根据显像原理不同可分为：1、非特异性肿瘤显像：根据显像结果又可分为：1）、非特异性阳性对比显像：利用放射性核素和核素标记物对肿瘤有亲和力而缺少特异性的一类药物显影，如99mTc-MDP骨显像、67Ga肿瘤显像、18F-FDG PET肿瘤显像等；2）、非特异性阴性对比显像：利用放射性核素药物对正常组织和肿瘤周围组织器官有亲和力，肿瘤部位出现相对无放射性药物的聚集而观察肿瘤玉林银丰国际中药港如99mTc-胶体肝脾显像、99mTcO4甲状腺显像等。2、特异性肿瘤显像：某些放射性药物能选择性的浓聚在特定的肿瘤中，如131I显像诊断分化型甲状腺癌及转移灶、131I-MIBG嗜铬细胞瘤显像、放免显像、受体显像等。 核素显像的基本条件是：1.能够选择性聚集在特定脏器或病变的各种放射性显像剂；能够探测脏器和病变中聚集的放射性并将之显示成像的核医学显像仪器。现在最常用的仪器为γ相机及SPECT(单光子发射计算机断层)。正电子发射计算机断层显像(PET)及PET/CT是核医学目前最先进的仪器,它是利用构成人体元素的放射性核素进行显像，能非创伤性检测人体脏器的生理病理功能、受体分布及变化、生化代谢状态及局部血流分布。 近年来，随着分子核医学的兴起，PET、PET-CT、多肽受体显像的迅速发展，前哨淋巴结等新技术的出现，使肿瘤核医学越来越得到临床的认可。 肿瘤核素诊断 1、非特异性肿瘤显像 （1）、氟代脱氧匍萄糖（18F-FDG）正电子发射断层显像（PET）及PET/CT肿瘤显像：用正电子放射性核素标记药物即正电子放射性药物进行显像。最常用的显像剂是反应匍萄糖代谢的氟代脱氧匍萄糖（18F-FDG）。PET及PET/CT肿瘤显像还可用其他很多正电子放射性药物进行显像，如氨基酸代谢显像剂；磷脂代谢显像剂；核酸代谢显像剂；乏氧显像剂；受体显像剂；抗体显像剂；细胞凋亡显像剂；肿瘤血管显像剂；血流灌注显像；基因显像等18F-FDG PET及PET/CT肿瘤显像主要用于下列几个方面：体内肿块的良恶性鉴别；恶性肿瘤的分期，恶性程度评估；寻找恶性肿瘤的复发、转移灶；对治疗的反应，疗效监测；寻找肿瘤原发灶；观察肿瘤疗后有无残存活的肿瘤细胞等。 18F-FDG PET对各种肿瘤诊断的灵敏度、特异性各异，有人对一万多例肿瘤患者进行分析后发现，FDG-PET对恶性肿瘤诊断的灵敏度为84%-87%，特异性为88%-93%，准确性87%-90%。 PET/CT是将PET和CT装在同一机架上，有机的融合于一体。病人一次扫描可获得全身的功能图像和解剖图像及融合图像，CT能对PET图像进行衰减校正，缩短了采集时间；CT 能提供解剖结构信息、定位诊断，与PET结合，提高了对恶性肿瘤诊断的特异性和准确性。 （2）、骨显像的异常影像及临床意义：骨局部放射性增高: 放射性较对侧和邻近骨组织增高的区域称"热区",可见于各种骨骼疾病。中国生物治疗网https://www.wendangku.net/doc/4b18050522.html,杨教授特别指出，肺癌的早期症状骨局部放射性减低: 减低区称"冷区",较为少见,可见于骨转移、骨囊肿、股骨头无菌性坏死等。超级影像: 肾脏不显影,骨显像剂聚集在骨组织明显增加,对恶性肿瘤患者,这种影像提示广泛转移的可能,也是骨代谢病表现之一。代谢性骨病骨显像特征:
肿瘤的发生发展与炎症
中国新药杂志2010[基金项目] 国家 重大新药创制 科技重大专项(2009ZX09301 010)[作者简介] 吉登波,女,博士后,主要从事基于炎症相关性肿瘤的药物研究。联系电话:(010)82801161,E m ai:l ji dengbo @b j m u .edu.c n 。[通讯作者] 崔景荣,女,博士生导师,教授,主要从事肿瘤药理学研究。联系电话:(010)82802467,E m ai:l j rcu@i b j m https://www.wendangku.net/doc/4b18050522.html, .cn 。 综述 肿瘤的发生、发展及治疗与炎症的关系 吉登波,崔景荣 (北京大学药学院天然药物及仿生药物国家重点实验室,北京100191) [摘要] 炎症与肿瘤的发生、发展具有相关性,它们通过内源性及外源性两条通路相互联系。炎症调 节因子和效应细胞是肿瘤组织局部微环境的重要组成,它们在炎症与肿瘤相互关系中起着重要作用。肿瘤微环境中的炎症有多种促肿瘤作用,可以促进恶性细胞的增殖和存活,促血管新生和转移,削弱机体的获得性免疫反应,改变机体对激素和化疗药物的反应。肿瘤相关性炎症的通路的揭示,可以为进一步改进肿瘤诊断和治疗提供新的靶分子。理想的靶向于肿瘤相关性炎症的药物可以转化促肿瘤炎症浸润,阻止炎症细胞移行到肿瘤灶,将促肿瘤微环境调整为抑制肿瘤的微环境,增强特异的获得性免疫反应,抑制肿瘤生长、存活和转移播散。 [关键词] 肿瘤;炎症;肿瘤相关性炎症 [中图分类号]R730.23 [文献标志码]A [文章编号]1003-3734(2010)17-1551-05 R el ati onsh i p bet w een the i nitiati on ,develop m ent and therapy of tu m or and i nfl a mm ation JI Deng bo ,C U I Ji n g r ong (StateK ey Laboratory o f Natural and B io m i m etic Drugs ,S chool of Phar maceutical Sciences , P ek ing Un i v ersit y ,B eijing 100191,China ) [Abstract] Infla mm ato r y diseases are assoc i a ted w it h the initiation and deve l o pm ent o f cancers .They are li n ked by i n tri n sic and ex tri n sic pathw ays .I nfla mm ation regulati n g factors and effector cells are i m portant co m po nents of m icroenv ironm ent i n tum or tissue ,wh ich have i m portan t ro le in the connection bet w een t h e i n fla mm ation and tu m o r .Infla mm ati o n i n the tum or m icroenv ironm en t has m any tum or pro m oting effects suc h as enhancing the pro liferati o n and surv i v al of tum or cells ,i n creasi n g ang i o genesis and m etastasis ,allev iati n g adaptive i m m une re sponse ,chang i n g reactions to hor m ones and che m otherapeuti c dr ugs .To reveal the pat h w ay about tum or related i n fla mm ati o n w ill g ive ne w tar getsw h ic h can i m prove the diagnosis and therapy .Antic i p ant drugs that tar get cancer re lated infla mm ati o n could transfor m a tumo r pro m oting infla mm atory i n filtrate ,prevent i n fla mm a tory ce lls fro m m i grati n g to the tum or site ,ad j u st a tum or pro m oti n g m icroenv ironm ent to beco m e a t u m or inhibiti n g m icroenv iron m ent ,enhance tum or specific adapti v e i m m une responses and i n h i b it the tum or proliferation ,sur v ival and m etasta t ic spread . [K ey w ords] tum or ;infla mm ation;t u m or related i n fla mm ation 炎症与肿瘤相互关系的研究始于19世纪。研究发现慢性炎症病灶常继发肿瘤发生,而肿瘤组织活检样本中存在炎症细胞。流行病学研究证实, 25%的肿瘤由炎症发展而来,炎症与肿瘤的发生具有相关性[1] 。与此相一致的是,用非类固醇类抗炎 药物可以降低某些肿瘤的发病率和死亡率[2] 。肿瘤相关性炎症的标志包括肿瘤组织中炎症细胞和炎症调节因子、与慢性炎症反应中相似的组织重塑和血管新生以及组织修复。一些与炎症相互关系还未确定的肿瘤中也可见这些炎症标志(如乳腺癌)。实际上,无论炎症细胞和调节因子是否促进
感染_炎症与肿瘤的发生_朱元民
doi：10．3969/j．issn．1006-5709．2013．02．003 感染、炎症与肿瘤的发生 朱元民，刘玉兰 北京大学人民医院消化内科，北京100044 【摘要】全球新发癌症患者中约17%是由感染性因素所致，本文介绍了感染、炎症与肿瘤发生的相关发病机制，一些常见的细菌、病毒感染与肿瘤发生的研究进展，并介绍及展望了一些研究成果在肿瘤预防、治疗的应用情况。 【关键词】感染；炎症；癌；肿瘤发生 中图分类号：R57文献标识码：A文章编号：1006－5709（2013）02－0105－04收稿日期：2012-10-15 Infections，inflammation and tumorigenesis ZHU Yuanmin，LIU Yulan Department of Gastroenterology，People’s Hospital，Peking University，Beijing100044，China 【Abstract】Approximately17%cases of the worldwide incidence of cancer can be attributed to bacterial or virus in-duced infections．In this article，we review the pathogenesis of tumorigenesis related with infections and inflammation，the new progress in the researches of the common viral and bacterial pathogens and the related cancers，we also review and prospect the favoring implications to prevent or treat the related cancers． 【Key words】Infections；Inflammation；Cancer；Tumorigenesis 恶性肿瘤的发病率在世界范围内越来越高，对人类健康及生命的威胁也愈加严重，2008年全球癌症新发病例约为1270万，癌症死亡例数为760万，预计全世界癌症死亡人数将继续上升，到2030年将超过1100万；另一方面，恶性肿瘤的发生是一个漫长的过程，可防可控，因而世界卫生组织在2006年正式将肿瘤列入慢性病的范畴。近年来的研究证明，感染、炎症与一些肿瘤的发病有着密切的关系。一些病毒、细菌和支原体等在机体的慢性感染可以促进肿瘤的发生，如人乳头状瘤病毒（HPV）与子宫颈癌、乙型肝炎病毒（HBV）与肝癌、幽门螺杆菌（H．pylori）与胃癌的发病均密切相关。全球新发肿瘤患者中约17%是由感染因素所致，在发展中国家这一比例更高，达26%，在发达国家的比例则更低，为7．2%［1］。胃癌、肝癌、宫颈癌等感染相关性癌在我国均是发病率较高的恶性肿瘤，尤其胃癌及肝癌高居我国恶性肿瘤的发病率前3位，因而重视感染因素在恶性肿瘤的发病中的作用，对恶性肿瘤的预防、诊断及治疗等方面均有重要意义。 1感染、炎症与肿瘤的发生机制 HPV、HBV、H．pylori等致病原在人群中都有较高的感染率，在人体相关组织中长期存在，可在局部形成慢性炎症，引起临床或亚临床表现。慢性炎症可以促进癌症的发生和发展，并参与癌症的发生、生长和转移的各个病理过程。早在两千年前古人就怀疑炎症和肿瘤相关，此后不断进行着观察和研究，目前感染、炎症可以导致肿瘤发生已找到大量的动物实验及临床研究的证据，如与炎症因素相关的结肠癌称之为炎症相关性结肠癌（colitis-assocated cancer，CAC），并建立了一些成熟的动物模型，也已发现一些炎症促进肿瘤的传导途径和关键分子，如核转录因子κB（nuclear tran-scription factor kappa B，NF-κB）及其活化激酶（IKK）系统、信号转导子与转录激活子3（signal transducen and activator of transcription，STAT3）等系统。一般认为炎症对肿瘤发生的影响主要与炎症局部细胞释放细胞因子和氧化游离基产生过多有关，还与炎症诱发的基因变异及免疫抑制等有关。 1．1炎症相关细胞因子与肿瘤发生的关系感染可激活和募集大量白细胞，如中性粒细胞、单核细胞、嗜酸性粒细胞、树突状细胞、肥大细胞等，聚集在感染部位，分泌各种细胞因子，包括炎症因子、趋化因子、黏附分子、生长因子等，如白细胞介素-6因子（IL-6）、IL-10、肿瘤坏死因子α（TNF-α）、血小板源性生长因子（PDGF）、表皮生长因子（EGF）、成纤维细胞生长因子（FGF）、血管内皮生长因子（VEGF）、活性氧簇（reac-tive oxygen species，ROS）、活性氮簇（reactive nitrogen species，RNS）及花生酸类等物质，一起组成新的炎症环境，另外炎细胞也可分泌蛋白溶解酶，这些炎症介质可在肿瘤的发生、发展过程中起重要作用，并刺激肿瘤细胞生长，血管和淋巴管生成以及肿瘤的浸润转移。 细胞因子对炎症的影响既可表现为促炎作用（pro-inflammation），也可表现为抗炎作用（anti-inflam-mation），促炎作用的细胞因子如IL-1、IL-8、IL-6、TNF- 通讯作者：刘玉兰，E-mail：liuyulan@pkuph．edu．cn
原发性肝癌与炎症关系的研究进展
原发性肝癌与炎症关系的研究进展 摘要原发性肝癌是最常见的恶性肿瘤之一，与炎症密切相关。在我国，肝癌患者中约大多数有慢性乙型病毒性肝炎感染病史；在欧美及日本，肝癌与丙型病毒性肝炎有关。本文总结原发性肝癌与炎症关系的最新研究进展，探讨多种炎症介质对肝癌发生、转移的促进机制，通过阻断相关炎症介质作用，探索出抑制原发性肝癌的发生、发展，减少复发、转移的新治疗途径。 原发性肝癌（primary hepatic carcinoma PHC）是世界卫生组织公布的十大恶性肿瘤之一，全世界每年新发及死亡病例约占所有恶性肿瘤的5.4%。最新的流行病学调查结果显示，其发病率及死亡率均有上升趋势。原发性肝癌是一种与炎症密切相关的恶性肿瘤，炎症在肝癌的发生和转移过程中具有促进作用[1][2]。本文就原发性肝癌与炎症关系的研究作一综述。 概述 Rudolph Virchow[3]第一次提出炎症在恶性肿瘤进展中起一定的作用，认为慢性炎症可促进肿瘤的生长；随后Wiemann B[4]证明：通过给患者注射化脓性链球菌和粘质沙雷菌引起的急性炎症可使部分患者的恶性肿瘤退化。目前炎症与肿瘤关系的研究成为热点。 大量流行病学调查提示：炎症是导致肿瘤发生或促进肿瘤发展的最主要因素之一，约20%的恶性肿瘤由炎症诱发或促进[1] [2] [5]。炎症与肿瘤发展的多个环节相关，包括肿瘤细胞形成、进展、逃逸、增生、浸润、血管生成、转移。炎症引起恶性肿瘤的分子和细胞机制尚未完全明确，有研究认为：炎症发生后，炎性细胞在迁入炎症部位的过程中产生大量的活性氧、活性氮物质，而且在慢性炎症过程中，内生抗氧化机制的抑制作用也可以产生超负荷的活性物质，这些活性物质诱导DNA损伤，破坏增生细胞的基因稳定性，最终在炎症和活性物质的反复破坏下，细胞基因改变，包括点突变、基因缺失、基因重组[6]。 在我国，原发性肝癌患者中约1/3有明确的乙型病毒性肝炎病史，欧美及日本，肝癌主要与丙型肝炎病毒感染及酒精性肝病有关。肝癌与肝炎病毒、酒精性肝病的关系，国内外已有大量研究，部分机制已经阐明。研究证实：乙型肝炎病毒（HBV）是一种DNA病毒，它可以整合插入宿主基因组，改变宿主体细胞基因的表达，导致宿主细胞基因组的不稳定，易发生基因改变，从而转化为肝癌细胞[7]；丙型肝炎病毒（HCV）为单链RNA病毒，可以和多种细胞蛋白作用，促进肝细胞向肝癌细胞转化[8]；酒精性肝病诱导肝癌形成过程中，酒精产物乙醛可直接损伤肝细胞或乙醇代谢产生的反应性氧化剂和脂质过氧化物直接造成DNA损伤[9]。原发性肝癌通常发生在慢性肝损伤的基础上，包括慢性肝炎、肝硬化，这些被认为是癌前病变。慢性肝损伤引起的炎症反应促进肝硬化的发展，并且激活了肝细胞的再生能力[10]。肝脏的修复机制若被短暂的激活，肝脏的结构和功能可迅速恢复，修复机制的持续激活可促进肝癌的形成和发展，肝炎病毒感染和长期饮酒可激活先天性免疫功能，维持持久的炎症反应，从而促进肝癌的形成和发展[11]。 目前研究已证明，在炎症与癌症的关系中，许多炎症介质具有重要作用。炎症介质产生于炎症反应过程中，也可以由肿瘤细胞产生，其中起关键作用的炎症介质包括环氧化酶-2（cyclooxygenase-2，Cox-2）、核转录因子—kappaB（NF-kB）、肿瘤坏死因子（TNF-α）、补体系统。. 原发性肝癌与Cox-2 环氧化酶（cyclooxygenase，Cox）是花生四烯酸转变为前列腺素的限速酶，又称前列腺素内过氧化物合成酶，是一种完整的膜结合蛋白，至少有三种形式：Cox-1位于内质网，属于结构型基因，多种正常组织
炎症与肿瘤发生(版本2)
炎症与肿瘤发生 炎症反应是针对机体损伤和感染的生理和病理反应。它主要分为急性和慢性两种，前者主要在物理、化学或急性感染情况中发生，是机体的早期防御措施，通常情况下可很快自愈；后者主要发生于慢性感染或自身免疫疾病中，此时机体的正常反馈调节已无法终止炎症，最终导致炎症慢性化。约有25%恶性肿瘤的发生与慢性炎症和感染有关，如肠癌和过敏性肠炎，肺癌和矽肺病，食管癌和慢性反流性食管炎等。种种证据表明，慢性炎症对肿瘤的起始、生长和恶化都起到了促进作用1。 1.炎症反应与肿瘤的发生 组织损伤包括化学性，物理性或感染均能够引起炎症反应。炎症反应通过释放炎症因子，募集吞噬细胞，嗜酸性粒细胞，肥大细胞和白细胞清除损伤的细胞或病原体。慢性炎症提供的微环境，为肿瘤的发生提供了条件2。在结肠癌、胃癌和肝癌等多种癌症发生过程中，炎症引起的氧化应激反应起到了促进作用3。炎症反应中募集的吞噬细胞和白细胞通过产生过氧化物和活性氮诱导DNA损伤，从而引起基因突变，删除和重排，进而引起肿瘤的发生4。 促炎因子的大量分泌是慢性炎症反应过程的标志之一，同时也对肿瘤的发生发展起到至关重要的作用。下面将介绍几种关键的促炎因子，以及它们在肿瘤发生发展过程中的调节作用。IL-6通过引起DNA甲基化降低了肿瘤抑制基因和DNA修复基因的表达，进而促进了肿瘤的发生5。IL-6及其下游靶标与细胞增殖、代谢等过程紧密相关，提示了它对肿瘤发生的贡献。胰腺中原癌基因Kras的表达激活了Stat3/Socs3信号通路，此过程依赖于IL-6及其下游信号通路，最终促进了胰腺癌的发生6。IL-6 激活的STAT3 属于STAT家族是一类转录因子，参与调控细胞生长、增殖。STAT3参与多种实体肿瘤的发生发展，据报道，超过70%的实体肿瘤发生过程中，都观察到STAT3活性的升高7。临床上，IL-6单抗Siltuximab在多种肿瘤的治疗中也通过了临床一期实验，目前临床二期实验正在进行8。 IL-1：IL-1家族IL-1α，IL-1β。有关IL-1与肿瘤的关系已有很多报道，IL-1对肿瘤的促进机制也相对完善，主要包括IL-1诱导促转移因子的表达，刺激相邻细胞产生血管生成蛋白和生长因子。在临床上，病人血清中IL-1水平的升高也与肿瘤恶化过程密切相关9。IL-8又叫CXCL8，是CXC促炎趋化因子家族成员，可以结合CXCR1和CXCR2两种G蛋白偶联受体，而这两种受体在多种肿瘤细胞表面都有表达。多种动物模型结果显示，IL-8参
炎症和肿瘤
肺转移性肝癌是指 所选答案： B. 肝癌转移至肺 正确答案： B. 肝癌转移至肺 问题 2 内脏器官急性炎症无意义的临床表现是 所选答案： E. 功能障碍 正确答案： E. 功能障碍 问题 3 肿瘤血道播散最常见的部位是 所选答案： E. 肝、肺 正确答案： E. 肝、肺 问题 4 下列哪项不属于渗出性炎 所选答案： C. 肉芽肿性炎 正确答案： C. 肉芽肿性炎 问题 5 原位癌的概念是 所选答案： D. 限于上皮内的癌，未突破基底膜 正确答案： D. 限于上皮内的癌，未突破基底膜
问题 6 良、恶性肿瘤最显著的区别在于 所选答案： A. 是否浸润和转移 正确答案： A. 是否浸润和转移 问题 7 关于血管瘤下列哪一项是错误的 所选答案： D. 肿瘤周围有纤维性包膜 正确答案： D. 肿瘤周围有纤维性包膜 问题 8 肿瘤对放射治疗和化疗的敏感性取决于 所选答案： A. 瘤细胞生长分数 正确答案： A. 瘤细胞生长分数 问题 9 癌与肉瘤最主要的区别是 所选答案： E. 来源于不同类型的组织 正确答案： E. 来源于不同类型的组织 问题 10 关于脓肿的叙述，下列哪项是正确的？ 所选答案： C. 为局限性化脓性炎 正确答案： C. 为局限性化脓性炎 问题 11 目前诊断肿瘤最可靠、准确性最高的方法是
所选答案： B. 活体组织检查正确答案： B. 活体组织检查 问题12 下列哪种肿块的形状提示是恶性肿瘤的可能性大所选答案： E. 火山口状 正确答案： E. 火山口状 问题13 下列哪项是恶性肿瘤的主要特征 所选答案： D. 浸润性生长和转移 正确答案： D. 浸润性生长和转移 问题14 下列关于炎症描述哪一项不正确 所选答案： C. 白细胞的渗出只见于急性炎症早期 正确答案： C. 白细胞的渗出只见于急性炎症早期 问题15 下列疾病中，哪一项属于化脓性炎症？ 所选答案： E. 小叶性肺炎 正确答案： E. 小叶性肺炎 问题16 关于未分化癌，下列叙述哪项正确？
炎症与肿瘤关系及其临床意义
旦匪壁堡垄查！！！！生！旦蔓！！鲞墨！塑！！！』墼！丛！：』！！！！型！！！！！∑型：！！：堕！：！ 炎症与肿瘤关系及其临床意义 童岳阳金美玲 【摘要】慢性炎症中持续的氧化应激导致ＤＮＡ损伤并抑制损伤后修复。致使抑癌基因失活；微环境中炎症细胞以及炎症因子诱导多种细胞因子表达；炎症细胞和细胞因子及其下游产物通过抑制细胞凋亡，促进血管新生，诱导机体免疫耐受等多种方式促进肿瘤的发生、发展、转移。其中多个重要环节已得到详细阐述．并成为肿瘤治疗的靶点。本文就炎症与肿瘤的关系及其Ｉ临床意义作一综述。 【关键词】炎症；肿瘤 Ｒｅｌａｔｉｏｎｓｈｉｐｂｅｔｗｅｅｎｉｎｆｌａｍｍａｔｉｏｎａｎｄｃａｎｃｅｒａｎｄｉｔｓｃｌｉｎｉｃａｌｓｉｇｎｉｆｉｃａｎｃｅ ＴＯＮＧＹｕｅ—ｙａｎｇ，）ｌＮＭｅｉ—ｌｉｎｇ．ＤｅｐａｒｔｍｅｎｔｏｆＲｅｓｐｉｒａｔｏｒｙＭｅｄｉｃｉｎｅ。ｔｈｅＡｆｆｉｌｉａｔｅｄＺｈｏｎｇｓｈａｎＨｏｓｐｉｔａｌｏｆＦｕｄａｎＵｎｉｖｅｒｓｉｔｙ·Ｓｈａｎｇｈａｉ２０００３２．凸ｉｎａ ［Ａｂｓｔｒａｃｔ］Ｓｕｓｔａｉｎｅｄｏｘｉｄａｔｉｖｅｓｔｒｅｓｓｉｎｔｈｅｐｒｏｃｅｓｓ０ｆｃｈｒｏｎｉｃｉｎｆｌａｍｍａｔｉｏｎｌｅａｄｓｔｏＤＮＡｄａｍａｇｅａｎｄｉｎｈｉｂｉｔｉｏｎｏｎｉｔｓｒｅｐａｉｒ，ｒｅｓｕｌｔｉｎｇｉｎｉｎａｃｔｉｖａｔｉｏｎｏｆｔｕｍｏｒｓｕｐｐｒｅｓｓｏｒｇｅｎｅｓ．Ｉｎｆｌａｍｍａｔｏｒｙｃｅｌｌｓａｎｄｉｎｆｌａｍｍａｔｏｒｙｆａｃｔｏｒｓｉｎｔｈｅｍｉｃｒｏ－ｅｎｖｉｒｏｎｍｅｎｔｃａｎｉｎｄｕｃｅ ｔｈｅｅｘｐｒｅｓｓｉｏｎｏｆａｖａｒｉｅｔｙｏｆｃｙｔｏｋｉｎｅｓ．Ｔｈｅｓｅｉｎｆｌａｍｍａｔｏｒｙｃｅｌｌｓ，ｃｙｔｏｋｉｎｅｓａｎｄｔｈｅｉｒｄｏｗｎｓｔｒｅａｍｐｒｏｄｕｃｔｓｐｒｏｍｏｔｅｔｈｅｏｃｃｕｒｒｅｎｃｅ，ｄｅｖｅｌｏｐｍｅｎｔａｎｄｍｅｔａｓｔａｓｉｓｏｆｃａｎｃｅｒｂｙｖａｒｉｏｕｓｗａｙｓ，ｓｕｃｈａｓｉｎｈｉｂｉｔｉｎｇａｐｏｐｔｏｓｉｓ，ｐｒｏｍｏｔｉｎｇａｎｇｉｏｇｅｎｅｓｉｓａｎｄｉｎｄｕｃｉｎｇｉｍｍｕｎｅｔｏｌｅｒａｎｃｅ．Ｓｅｖｅｒａｌｉｍｐｏｒｔａｎｔｌｉｎｋｓｈａｖｅｂｅｅｎｄｅｓｃｒｉｂｅｄｉｎｄｅｔａｉｌ，ａｎｄｂｅｃｏｍｅｔｈｅｔａｒｇｅｔｓｏｆｃａｎｃｅｒｔｈｅｒａｐｙ．Ｔｈｅｒｅｆｏｒｅ，ｔｈｅｒｅｌａｔｉｏｎｓｈｉｐｂｅｔｗｅｅｎｉｎｆｌａｍｍａｔｉｏｎａｎｄｃａｎｃｅｒａｎｄｉｔｓｃｌｉｎｉｃａｌｓｉｇｎｉｆｉｃａｎｃｅａｒｅｒｅｖｉｅｗｅｄ．［：Ｋｅｙｗｏｒｄｓ］Ｉｎｆｌａｍｍａｔｉｏｎ；Ｃａｎｃｅｒ １００多年前，德国学者Ｖｉｒｃｈｏｗ就提出肿瘤起 源于慢性炎症部位的假说［１］。炎症与肿瘤之间的关 系已经得到广大学者的高度重视，随着研究的不断 深入，许多细胞和分子水平的证据揭示了两者间复 杂的联系。本文就炎症与肿瘤的关系及其临床意义 作一综述。 １炎症相关性肿瘤 现已证实多种肿瘤的发生、发展与炎症相关，与 炎症有关的肿瘤约占所有恶性肿瘤的１９％，每年全 球有超过２００万人发生炎症相关性肿瘤ｒ２］。如长期 吸入石棉导致慢性炎症与间皮瘤发生有关，长期吸 入二氧化硅、吸烟、支气管哮喘引起的慢性炎症与肺 癌的形成相关，幽门螺杆菌感染引起的胃炎、胃溃疡 与消化道腺癌相关，乙型、丙型肝炎病毒引起的慢性 肝炎与肝癌相关。随着炎症与肿瘤关系研究的进一 ＤＯＩ：１０．３７６０／ｅｍａ．ｊ．ｉｓｓｎ．１６７３—４３６Ｘ．２００９．０２．０１ｌ 作者单位：２０００３２上海，复旦大学附属中山医院呼吸科．综述． 步深入，更多与肿瘤相关的慢性感染被提出。 Ｌｉｔｔｍａｎ等通过６项流行病学研究发现，衣原体感 染血清学检查阳性的人群具有更高的罹患肺癌的 风险ｏＪ。 ２炎症与肿瘤的发生、发展 机体创伤修复或者病原体入侵时，免疫系统被 激活并且招募大量炎症细胞至损伤部位，后者分泌 多种细胞因子（包括炎症因子、趋化因子、黏附分 子），与细胞外基质在局部形成新的微环境。微环境 中的细胞因子等可能通过以下途径促进肿瘤发生、 发展和转移：刺激血管新生和血管新生因子生成；导 致ＤＮＡ损伤并抑制损伤后修复；抑癌基因功能失 活；对恶性细胞的旁分泌生长和维持生存作用；增加 血管通透性；调节基质金属蛋白酶影响肿瘤细胞的 浸润、转移；诱导／激活基质，重建组织；直接或间接 控制肿瘤细胞迁移；调节白细胞浸润；调节细胞间黏 附分子；改变宿主免疫反应。正常情况下，在促炎因 子之后，机体将产生抗炎细胞因子，使炎症呈自限万方数据