The authors have declared that no competing interests exist.
Conceived and designed the experiments: QWZ LL CYG YQW. Performed the experiments: YHZ HSS YWZ XZW. Analyzed the data: YHZ HSS YWZ. Contributed reagents/materials/analysis tools: QWZ LL YHZ. Wrote the paper: QWZ CYG.
Tumor associated macrophages (TAMs) are considered with the capacity to have both negative and positive effects on tumor growth. The prognostic value of TAM for survival in patients with solid tumor remains controversial.
We conducted a meta-analysis of 55 studies (n = 8,692 patients) that evaluated the correlation between TAM (detected by immunohistochemistry) and clinical staging, overall survival (OS) and disease free survival (DFS). The impact of M1 and M2 type TAM (n = 5) on survival was also examined.
High density of TAM was significantly associated with late clinical staging in patients with breast cancer [risk ratio (RR) = 1.20 (95% confidence interval (CI), 1.14–1.28)] and bladder cancer [RR = 3.30 (95%CI, 1.56–6.96)] and with early clinical staging in patients with ovarian cancer [RR = 0.52 (95%CI, 0.35–0.77)]. Negative effects of TAM on OS was shown in patients with gastric cancer [RR = 1.64 (95%CI, 1.24–2.16)], breast cancer [RR = 8.62 (95%CI, 3.10–23.95)], bladder cancer [RR = 5.00 (95%CI, 1.98–12.63)], ovarian cancer [RR = 2.55 (95%CI, 1.60–4.06)], oral cancer [RR = 2.03 (95%CI, 1.47–2.80)] and thyroid cancer [RR = 2.72 (95%CI, 1.26–5.86)],and positive effects was displayed in patients with colorectal cancer [RR = 0.64 (95%CI, 0.43–0.96)]. No significant effect was showed between TAM and DFS. There was also no significant effect of two phenotypes of TAM on survival.
Although some modest bias cannot be excluded, high density of TAM seems to be associated with worse OS in patients with gastric cancer, urogenital cancer and head and neck cancer, with better OS in patients with colorectal cancer.
Macrophages are a population of innate myeloid cells that are released from bone marrow as immature monocytic precursors and, after circulating in the blood stream, migrate into different tissues to undergo specific differentiation depending on local cues in the tissue
In 1863, it was fist found that a major leukocyte population was present in tumor, the so-called tumor-associated macrophages (TAM), which reflect the onset of cancer at site of previous chronic inflammation
For long a large number of studies have been focused on identifying the prognostic value of TAM in solid tumors and most studies suggest that TAM is beneficial for tumor growth and, therefore, associated with poor prognosis
We performed our meta-analysis according to a predetermined written protocol. To be eligible for our meta-analysis, studies had to deal with solid tumor at inclusion, to evaluate the correlation between TAM and survival, and to be published in English or Chinese languages. A computer-aided literature search of Pubmed (MEDLINE) 1950-present and EMBASE was conduced by combing search terms “cancer”, ”tumor”, “neoplasm”, “carcinoma”, “tumor-associated macrophage”, “tumor-infiltrating macrophage” and “intratumoral macrophage.” The deadline of the included articles was April 20th, 2012. Reference list from primary identified studies were also searched to prevent missing any studies by the electronic search strategies.
Inclusion criteria for primary studies were as follows: (1) proven diagnosis of solid tumor in humans, (2) using immunochemistry method to evaluate TAM by anti-CD68, M1-type TAM by anti-HLA-DR and M2-type TAM by anti-CD163, and (3) correlation of TAM with TNM staging, OS or DFS. Two independent reviewers processed primary assessment by identifying the eligibility of abstracts from database. Full articles were retrieved for further assessment if the eligibility was unclear from the abstracts. Any disagreements were resolved by serious discussion. We carefully examined the names of all authors and the medical centers involved in each publication to avoid duplication data. Whenever studies pertained to overlapping patients, we retained the studies with highest number of patients.
We used preconcerted rules to standardize as much as possible the definition of TAM positivity. As 20% was the used as a cutoff value in majority of the included studies
Data were carefully extracted from all of the included studies in duplicate by two of us, using a standard information collection form, with the following items, first author, year of publication, study design, median follow-up time, country of origin, number of patients involved, number of men included, mean or median age, tumor location, histological type, tumor-node-metastasis (TNM) staging, blinded reading, definition of TAM high, anti-cancer treatment(s) during follow up, OS or DFS or both. The main outcomes were tabulated in 2×2 tables showing the TNM staging status, occurrence or not of death or disease during follow-up according to TAM results.
Included studies were divided into three groups for analysis: those with data regarding TNM staging, those regarding OS and those regarding DFS. A study was considered significant when the P for comparing survival distribution between groups with high and low TAM was inferior to 0.05. A study was termed “positive” when a high TAM predicted a late clinical staging or poorer survival, “negative” when a high TAM predicted a early clinical staging or better survival, “indeterminate” when no significant relationship between TAM and clinical staging or survival was found.
For the quantitative aggregation of survival result, impacts of TAM on survival were reported for individual studies by estimating RRs with 95% confidence interval values. We first simply extracted RR and their 95%CI from the original article. If not available, the published data including number of patients at risk and total number of events in each groups from articles were used to estimate RR according to the methods described by Parmer et al
The initial search algorithm retrieved a total of 3076 references and we evaluated 144 candidate studies in full text. Upon further review, 50 articles were eliminated due to inadequate data for meta-analysis and another 29 articles were out of scope because of evaluating other factors related to TAM (
The characteristics of included studies are listed in
First author (ref) | Year | Study design | n (M/F) | Tumor location | Tumor stage I/II (III/IV) | Median follow-up (y) | Blinded reading | Staining for TAM high | RR estimation | Analysis | Result |
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Khorana (29) | 2003 | Prosp. | 131 (69/53) | 131 Colon | 11 (118) | 5 | NR | >2% | Data extrapolated, Survival curve | Stag., OS | Indeterminate |
Tan (12) | 2005 | Retro. | 60 (35/25) | 60 Colon | 26 (34) | NR | NR | >25% | Data extrapolated, Survival curve | Stag., OS | Negative |
Bacman (30) | 2007 | NR | 310 (189/121) | 310 Colon | 178 (132) | 7.5 | NR | NR | Data extrapolated | OS | Indeterminate |
Forssell (15) | 2007 | Retro. | 488 (271/217) | 488 Colon | 207 (254) | NR | NR | NR | Data extrapolated, Reported in text | Stag., OS | Indeterminate, negative |
Zhou (18) | 2010 | NR | 160 (94/66) | 160 Colon | NR | 5 | Yes | 20% | Data extrapolated, reported in text | Stag., OS | Negative |
Ishigami (31) | 2003 | Retro. | 97 (72/25) | 97 Stom | 67 (30) | NR | NR | >200 / HPF | Data extrapolated, Survival curve | Stag., OS | Indeterminate, positive |
Ohno (10) | 2005 | Retro. | 84 (57/27) | 84 Stom | 41 (43) | NR | Yes | >4.7% | Survival curve | DFS | Negative |
Hass (32) | 2009 | Prosp. | 52 (40/12) | 50 Stom | 39 (13) | 5.9 | NR | NR | Reported in text | DFS | Indeterminate |
Kawahara (33) | 2010 | NR | 111 (77/34) | 111 Stom | 36 (75) | NR | NR | NR | Reported in text | OS | Positive |
Osinsky (34) | 2011 | Prosp. | 105 (71/34) | 105 stom | 48 (57) | NR | NR | >23.0% | Reported in text | OS | Positive |
Zhu (22) | 2008 | Retro. | 105 (96/9) | 105 Liver | 86 (19) | 1.84 | NR | >20% | Data extrapolated, reported in text | Stag., OS, DFS | Indeterminate, positive |
Li (24) | 2009 | Retro. | 302 (260/42) | 302 Liver | 237 (65) | 4.83 | NR | >20% | Data extrapolated, reported in text | Stag., OS, DFS | Indeterminate, negative |
Ding (35) | 2009 | Retro. | 107 (87/20) | 107 Liver | 98 (39) | 2.5 | MR | >23% | Reported in text | OS, DFS | Positive |
Kuang (36) | 2009 | Retro. | 262 (NR) | 206 Liver | 249 (13) | NR | NR | NR | Reported in text | OS, DFS | Positive |
Ju (23) | 2009 | Retro. | 130 (112/18) | 130 Liver | 66 (64) | 2.65 | NR | >20% | Reported in text | Stag., OS, DFS | Positive |
Koide (9) | 2002 | Retro. | 56 (42/14) | 56 Esophagus | 30 (26) | NR | NR | NR | Data extrapolated, survival cure | Stag., OS | Indeterminate, negative |
Guo (19) | 2007 | NR | 137 (103/34) | 137 Esophagus | 86 (51) | NR | NR | >25% | Reported in text | Stag., OS | Indeterminate, positive |
Kurahara (37) | 2012 | Retro. | 76 (52/24) | 52 Pancreas | 29 (47) | NR | Yes | NR | Survival curve | OS, OSb | Indeterminate |
Hasita (38) | 2010 | NR | 39 (27/12) | 55 Bile duct | 29 (10) | 3.33 | Yes | NR | Data extrapolated, survival curve | Stag., OS, DFS, Stag.b, OSb, DFSb | Indeterminate |
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Leek (39) | 1996 | Retro. | 101 (0/101) | 5 Breast | NR | NR | NR | MD > = 12 | Reported in text | OS, DFS | Positive |
Toi (40) | 1999 | NR | 229 (0/229) | 229 Breast | NR | 4 | Yes | NR | Survival curve | DFS | Indeterminate |
Valkovic (41) | 2002 | NR | 97 (0/97) | 97 Breast | 82 (15) | NR | NR | NR | Data extrapolated | Stag. | Indeterminate |
Bolat (42) | 2006 | Retro. | 78 (0/78) | 78 Breast | 38 (10) | NR | NR | NR | Data extrapolated | Stag. | Indeterminate |
Mahmound (43) | 2012 | Retro. | 1902 (0/1902) | 1902 Breast | 220 (1682) | NR | NR | NR | Data extrapolated, survival curve | Stag., DFS | Positive, indeterminate |
Salvesen (44) | 1999 | Prosp. | 60 (0/60) | 60 Endometrium | 50(10) | 11 | NR | NR | Data extrapolated, reported in text | Stag., OS | Positive, indeterminate |
Hashimoto (45) | 2000 | NR | 109 (0/109) | 109 Endometrium | 56(53) | 4.58 | NR | NR | Data extrapolated | Stag., DFS | Indeterminate |
Ohno (11) | 2004 | Retro. | 70 (0/70) | 70 Endometrium | NR | NR | NR | MD >10.7 | Survival curve | DFS | Negative |
Soeda (46) | 2008 | Retro. | 76 (0/76) | 76 Endometrium | 59(17) | 6.83 | NR | NR | Survival curve | OS, DFS | Positive, indeterminate |
Espinosa (47) | 2010 | NR | 64 (0/64) | 64 Endometrium | 23(26) | NR | NR | NR | Data extrapolated | Stag.b | Indeterminate |
Lissbrant (48) | 2000 | Retro. | 85 (85/0) | 85 Prostate | 75(10) | NR | NR | > = 0.97% | Survival curve | Stag., OS | Indeterminate |
Shimura (49) | 2000 | NR | 81 (81/0) | 81 Prostate | 67(13) | 3.9 | NR | NR | Reported in text | DFS | Indeterminate |
Nonomura (50) | 2011 | NR | 131 (131/0) | 131 Prostate | 30(41) | 2.9 | NR | MD > = 22 | Survival curve | DFS | Positive |
Heller (51) | 2002 | Retro. | 24 (0/24) | 24 Cervix | 20/4 | NR | NR | NR | Data extrapolated | Stag. | Indeterminate |
Kawanaka (52) | 2008 | Retro | 73 (0/73) | 73 Cervix | 22/51 | NR | Yes | MD > = 55 | Survival curve | DFS | Indeterminate |
Hanada (53) | 2000 | NR | 63 (51/12) | 63 Bladder | 42/21 | 5.4 | Yes | MD > = 67 | Data extrapolated, reported in text | Stag., OS | Positive |
Takayama (54) | 2009 | NR | 41 (38/3) | 41 Bladder | NR | 25 | NR | > = 4 | Reported in text | DFS | Positive |
Tanaka (55) | 2004 | NR | 89 (0/89) | 89 Ovary | 22/67 | 6.8 | NR | > = 25% | Data extrapolated, reported in text, survival curve | Stag., OS, DFS | Negative, positive, indeterminate |
Wan (25) | 2009 | NR | 67 (0/67) | 67 Ovary | 0/67 | NR | NR | >20% | Survival curve | OS | Positive |
Chai (20) | 2008 | NR | 99 (42/57) | 99 Uroth | NR | NR | NR | >20% | Reported in text | OS, DFS | Indeterminate, positive |
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Takanami (56) | 1999 | Retro. | 113 (66/47) | 113 Lung | 61/52 | NR | NR | MD>32 | Survival curve | OS | Positive |
Chen (57) | 2005 | NR | 41 (27/14) | 41 Lung | 23/18 | NR | NR | MD> = 163 | Survival curve | DFS | Indeterminate |
Welsh (13) | 2005 | Retro. | 175 (116/59) | 175 Lung | 123/38 | NR | Yes | NR | Data extrapolated | Stag., DFS | Negative |
Zeni (58) | 2007 | NR | 50 (43/7) | 43 Lung | NR | NR | NR | >16.3% | Reported in text, survival curve | Stag., OS | Positive |
Kawai (16) | 2008 | NR | 199 (139/60) | 199 Lung | NR | NR | NR | NR | Reported in text | OS | Negative |
Ohri (17) | 2009 | Retro. | 40 (16/24) | 40 Lung | 34/6 | NR | NR | NR | Survival curve | OS | Negative |
Al-shibli (59) | 2009 | Retro. | 371 (253/82) | 371 Lung | 303/32 | 8 | NR | > = 25% | Data extrapolated, survival curve | OS, DFS | Indeterminate |
Ma (26) | 2010 | NR | 50 (40/10) | 50 Lung | 33/17 | NR | NR | >20% | Reported in text | OSa, OSb | Indeterminate |
Ohtaki (60) | 2010 | Prosp. | 170 (85/85) | 170 Lung | NR | 10.1 | NR | NR | Data extrapolated | Stag., OS | Positive |
Zhang (61) | 2011 | Retro. | 65 (38/27) | 65 Lung | 38/27 | NR | Yes | TAM counts >102 | Survival curve | OS | Positive |
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Liu (21) | 2008 | NR | 112 (93/19) | 112 Oral | 50/62 | NR | NR | >20% | Data extrapolated, survival curve | Stag., OS | Positive |
Fujii (62) | 2012 | NR | 108 (31/10) | 108 Oral | 46/62 | NR | NR | > = 2/HPF | Data extrapolated, reported in text | Stag., stag.b, OSb | Positive, indeterminate, positive |
Peng (14) | 2006 | NR | 60 (38/22) | 60 Oral | 15/45 | NR | NR | > = 63.7/HPF | Data extrapolated | OS | Negative |
Lin (63) | 2011 | NR | 84 (77/7) | 84 Lar | 30/54 | NR | NR | > = 10/HPF | Data extrapolated, reported in text | Stag., OS, DFS | Indeterminate, indeterminate, positive |
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Ryder (64) | 2008 | NR | 37 (13/24) | 37 Thyr | 5/32 | NR | Yes | > = 10/HPF | Survival curve | OS | Positive |
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Burt (65) | 2011 | Retro. | 667 (531/136) | 667 Meso | 64/603 | NR | Yes | NR | Reported in text | OS | Indeterminate |
Of the included studies, 19 studies focused on gastrointestinal cancers, including colorectal cancer (N = 5), gastric cancer (N = 5), liver cancer (N = 5), esophagus cancer (N = 2), pancreatic caner (N = 1) and cholangiocarcinoma (N = 1). 20 studies analyzed the impact of TAM on survival in patients with urogenital cancers, including breast cancer (N = 5), endometrial cancer (N = 5), prostate cancer (N = 3), cervical cancer (N = 2), bladder cancer (N = 2), ovary cancer (N = 2) and urothelial cancer (N = 1). 5 studies mentioned the value of M2-type TAM on survival
As shown in
Clinical staging and survival data are reported as (
For overall population, high density of TAM was associated with a worse prognosis regarding overall survival (
Clinical staging and survival data are reported as (
For the overall population, no significant relation was observed between TAM and DFS [RR = 1.01 (95%CI, 0.99–1.04)](
The impact of TAM density on clinic-pathological in patients with different cancer was further analyzed and described in
Cancer type | Clinic-pathological factors | Number of studies | Number of total patients | HR (95% CI) | Results | Reference | |
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TNM Stage (I/II vs. III/IV) | 2 | 619 | 0.71 (0.35, 1.45) | 0.194 | Indeterminate | (15), (29) | |
T status (T1/T2 vs. T3/T4) | 2 | 191 | 0.35 (0.13, 0.90) | 0.246 | Positive | (12), (29) | |
Lymph node metastasis | 2 | 370 | 0.72 (0.13, 4.06) | 0.013 | Indeterminate | (12), (30) | |
Distant metastasis | 3 | 530 | 0.72 (0.24, 2.11) | 0.005 | Indeterminate | (12), (18), (30) | |
Histological grade (well/moderate vs. poor) | 3 | 858 | 0.26 (0.06, 1.06) | 0.005 | Indeterminate | (12), (15), (30) | |
Pathologic classification (mucinous vs. nonmucinous) | 2 | 648 | 2.53 (1.35, 4.73) | 0.675 | Negative | (15), (18) | |
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TNM Stage (I/II vs. III/IV) | 1 | 97 | 2.40 (0.98, 5.91) | NR | Indeterminate | (31) | |
T status (T1/T2 vs. T3/T4) | 1 | 97 | 1.36 (0.54, 3.46) | NR | Indeterminate | (31) | |
Lymph node metastasis | 2 | 149 | 0.39 (0.19, 0.80) | 0.302 | Positive | (31), (32) | |
Distant metastasis | 1 | 52 | 1.30 (0.40, 4.28) | NR | Indeterminate | (32) | |
Histological grade (well/moderate vs. poor) | 1 | 97 | 0.54 (0.22, 1.32) | NR | Indeterminate | (31) | |
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TNM Stage (I/II vs. III/IV) | 3 | 514 | 1.27 (0.84, 1.93) | 0.702 | Indeterminate | (22), (24), (35) | |
Vascular invasion (absent vs. present) | 3 | 514 | 1.38 (0.87, 2.21) | 0.410 | Indeterminate | (22), (24), (35) | |
Tumor differentiation | 2 | 409 | 1.08 (0.70, 1.66) | 0.956 | Indeterminate | (24), (35) | |
Tumor size (≤5 vs. >5cm) | 2 | 409 | 1.76 (1.19, 2.60) | 0.329 | Negative | (24), (35) | |
Hepatitis history (No vs. Yes) | 2 | 407 | 1.45 (0.80, 2.60) | 0.456 | Indeterminate | (22), (24) | |
Liver cirrhosis (No vs. Yes) | 3 | 514 | 1.18 (0.75, 1.88) | 0.886 | Indeterminate | (22), (24), (35) | |
Fibrous capsule (absent vs. present) | 3 | 514 | 0.83 (0.58, 1.19) | 0.750 | Indeterminate | (22), (24), (35) | |
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T status (T1/T2 vs. T3/T4) | 1 | 56 | 2.73 (0.70, 10.60) | NR | Indeterminate | (9) | |
Lymph node metastasis | 1 | 56 | 0.75 (0.21, 2.59) | NR | Indeterminate | (9) | |
Lymphatic invasion (absent vs. present) | 1 | 56 | 3.21 (0.81, 12.8) | NR | Indeterminate | (9) | |
Venous invasion (absent vs. present) | 1 | 56 | 6.22 (1.48, 26.1) | NR | Negative | (9) | |
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UICC stage (I/II vs. III/IV) | 1 | 55 | 3.31 (0.71, 15.4) | NR | Indeterminate | (38) | |
Histological grade (well/moderate vs. poor) | 1 | 55 | 5.25 (0.93, 29.7) | NR | Indeterminate | (38) | |
Lymph node metastasis | 1 | 55 | 1.06 (0.19, 6.05) | NR | Indeterminate | (38) | |
Vascular invasion (absent vs. present) | 1 | 55 | 2.13 (0.34, 13.2) | NR | Indeterminate | (38) | |
Tumor size (<4 vs. ≥4cm) | 1 | 55 | 1.38 (0.39, 4.87) | NR | Indeterminate | (38) | |
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TNM Stage (I/II vs. III/IV) | 1 | 78 | 1.20 (1.14, 1.28) | NR | Negative | (42) | |
Histological grade (I/II vs. III) | 3 | 2077 | 3.42 (2.71, 4.30) | 0.742 | Negative | (41), (42), (43) | |
Lymph node metastasis | 3 | 2077 | 1.29 (1.04, 1.62) | 0.604 | Negative | (41), (42), (43) | |
Tumor size (≤2 vs. >2cm) | 3 | 2077 | 1.43 (1.14, 1.80) | 0.963 | Negative | (41), (42), (43) | |
Vascular invasion (absent vs. present) | 1 | 1902 | 1.74 (1.35, 2.23) | NR | Negative | (43) | |
HER-2 status (negative vs. positive) | 1 | 1902 | 2.59 (1.75, 3.85) | NR | Negative | (43) | |
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FIGO stage (I/II vs. III/IV) | 2 | 169 | 2.34 (0.36, 15.39) | 0.021 | Indeterminate | (44), (45) | |
Lymph node metastasis | 1 | 109 | 0.43 (0.12, 1.53) | NR | Indeterminate | (45) | |
Myometrial invasion (negative vs. positive) | 1 | 109 | 2.09 (0.65, 6.69) | NR | Indeterminate | (45) | |
Histological grade (I/II vs. III) | 2 | 169 | 4.34 (0.70, 27.08) | 0.044 | Indeterminate | (44), (45) | |
Pathologic classification (Endometrioid vs.non-endometrioid) | 1 | 109 | 1.37 (0.41, 4.62) | NR | Indeterminate | (45) | |
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T status (T1/T2 vs. T3/T4) | 1 | 85 | 3.30 (1.56, 6.96) | NR | Indeterminate | (48) | |
Distant metastasis | 1 | 85 | 1.06 (0.25, 4.54) | NR | Indeterminate | (48) | |
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FIGO stage (I/II vs. III/IV) | 2 | 97 | 0.68 (0.06, 8.26) | 0.063 | Indeterminate | (51), (52) | |
Lymph node metastasis | 1 | 24 | 1.75 (0.26, 11.7) | NR | Indeterminate | (51) | |
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TNM Stage (I/II vs. III/IV) | 1 | 63 | 5.76 (1.76, 18.9) | NR | Negative | (53) | |
T status (T1/T2 vs. T3/T4) | 1 | 63 | 17.6 (4,34, 71.1) | NR | Negative | (53) | |
Distant metastasis | 1 | 63 | 12.4 (2.50, 61.0) | NR | Negative | (53) | |
Vascular invasion (absent vs. present) | 1 | 63 | 10.8 (1.26, 92.4) | NR | Negative | (53) | |
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TNM Stage (I/II vs. III/IV) | 1 | 89 | 0.52 (0.35, 0.77) | NR | Positive | (54) | |
Lymph node metastasis | 1 | 89 | 0.14 (0.05, 0.35) | NR | Positive | (54) | |
Tumor differentiation | 1 | 89 | 0.79 (0.34, 1.83) | NR | Indeterminate | (54) | |
Tumor size (≤5 vs. >5cm) | 1 | 89 | 0.94 (0.41, 2.17) | NR | Indeterminate | (54) | |
Histological type (serous vs. nonserous) | 1 | 89 | 0.81 (0.34, 1.9) | NR | Indeterminate | (54) | |
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Pathologic stage (I vs. II/III/IV | 2 | 345 | 1.29 (0.24, 6.78) | <0.001 | Indeterminate | (13), (60) | |
Tumor differentiation | 1 | 170 | 5.80 (2.99, 11.2) | NR | Negative | (60) | |
T status (T1/T2 vs. T3/T4) | 1 | 170 | 2.70 (1.40, 5.21) | NR | Negative | (60) | |
Lymph node metastasis | 1 | 170 | 2.72 (1.27, 5.82) | NR | Negative | (60) | |
Vessel invasion | 1 | 170 | 3.24 (1.69, 6.24) | NR | Negative | (60) | |
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TNM Stage (I/II vs. III/IV) | 2 | 220 | 2.53 (1.46, 4.38) | 0.888 | Negative | (21), (62) | |
T status (T1/T2 vs. T3/T4) | 2 | 220 | 2.33 (1.34, 4.03) | 0.328 | Negative | (21), (62) | |
Lymph node metastasis | 2 | 220 | 2.56 (1.46, 4.47) | 0.528 | Negative | (21), (62) | |
Tumor differentiation | 2 | 220 | 1.32 (0.68, 2.57) | 0.294 | Indeterminate | (21), (62) | |
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TNM Stage (I/II vs. III/IV) | 1 | 37 | 4.31 (0.42, 43.7) | NR | Indeterminate | (64) | |
Distant metastasis | 1 | 37 | 4.17 (0.66, 26.1) | NR | Indeterminate | (64) |
Both Begg's funnel plot and Egger's test were performed to assess the publication bias in all studies evaluating staging, OS, DFS separately, and evaluation was also performed in sub-group analysis. Begg's funnel plot did not reveal any evidence of significant asymmetry in the overall meta-analysis of staging (p = 0.679), OS (p = 0.065) and DFS (p = 0.792)(
(
So far, a group of original articles and reviews has studied the prognostic significance of TAM in solid tumors, and the presence of both significant and non-significant studies addressing the importance of TAM on survival made it necessary to perform a quantitative aggregation of the survival results. The present result showed that high density of TAM, as detected with immunohistochemistry, was significant associated with worse overall survival in solid tumor, with a global RR of 1.15. As potential bias exists between studies on different tumors, subgroup analysis was also performed, which suggested that high density of TAM was significant associated with OS in patients with gastric cancer [RR = 1.64 (95%CI, 1.24–2.16)], breast cancer [RR = 8.62 (95%CI, 3.10–23.95)], bladder caner [RR = 5.00 (95%CI, 1.98–12.63)], ovarian cancer [RR = 2.55 (95%CI, 1.60–4.06)], oral cancer [RR = 2.03 (95%CI, 1.47–2.80)] and thyroid cancer [RR = 2.72 (95%CI, 1.26–5.86)]. Moreover, there showed positive effect in patients with colorectal cancer [RR = 0.64 (95%CI, 0.43–0.96)]. However, no significant effect was seen between TAM and DFS.
When comparing the results of different types of tumors, several key differences were observed. As mentioned above, although macrophages under certain conditions can kill tumor cells, they can also play potential roles as tumor promoters to secrete a variety of factors that directly stimulate tumor invasion and metastasis. The combing effect of TAM on prognosis in patients with different tumors depends on stimulating factors from two opposite aspects in tumor environments. In this meta-analysis, we reach a conclusion that high TAM infiltration is associated with worsen prognosis in patients with urogenital cancer or gastric cancer, not all cancer type. In other hand, TAM showed antitumorigenic properties in combing 5 studies on colorectal cancer, resulting in improved prognosis.
To further investigate the prognostic value of TAM in different type of cancer, we analyzed the relation between the density of TAM and clinic-pathological factors that was also associated with outcome of cancer patients. As the density of TAM has a negative effect on survival in patients with gastric cancer, breast cancer, bladder cancer, ovary cancer, and oral squamous cell carcinoma, negative effects are also seen in clinic-pathological factors such as TNM staging (breast cancer, bladder cancer and oral squamous cell carcinoma), T status (breast cancer and oral squamous cell carcinoma), lymph node metastasis (breast cancer, bladder cancer and oral squamous cell carcinoma), and distant metastasis (bladder cancer), which contributed to tumor progression and patient survival. Interestingly, there also demonstrated a positive effect of TAM on lymph node metastasis in gastric and ovary cancer, which indicated that high density of TAM was associated with less probability of lymph node metastasis, however, significant negative effect was shown on overall survival. Thus, more studies are needed to clarify this ambivalent phenomenon. Contrary to tumors we mentioned above, our data suggested that an incremental increase in density of TAM improved overall survival in patients with colon cancer, with a homodromous effect on T status. There was also a trend towards lower rate of lymph node metastasis and distant metastasis in TAM rich tumors. In addition, a high density of TAM infiltration was found related to nonmucious type of colon cancer.
The mechanisms behind the oncogenic and anti-tumorigenic effects of TAMs have not been fully elucidated and a great number of studies have focused on explaining these apparently contradictory effects of TAM in different cancer outcome. The functions of TAM in different type of tumors are concerned as the most important determining factor to the prognosis, which are profoundly affected by microenvironmental signals and can range from powerful stimulation of inflammatory responses to induction of immunosuppression
Although the results of meta-analysis are considered as gold standards by authors worldwide
Second, macrophages can be identified by cell surface markers, expression of transcriptional factors, the production of cytokines and their functions in vitro
Third, variability in definitions, outcomes, measurements, experimental procedure, and even antibody concentration may contribute to heterogeneity between studies
In conclusion, it is clear that TAM has protumorigenic as well as antitumorigenic properties in solid tumor. As discussed above, there have been showed a “macrophage balance” on prognosis depending on the microenvironment of the tumor tissue in different type of solid tumor. It may be possible in the future to use or induce activated macrophages to restrain tumor growth and improve patient survival, through altering tumor microenvironment. Moreover, targeted therapies that uniquely strike macrophages may provide innovative therapeutic strategies against tumor progression.
We thank all authors whose publications could be included in our meta-analysis, and especially Prof. Liu G (Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, Chengdu, China), Nie Y (West China School of Medicine, Sichuan University, GuoXueXiang 37#, Chengdu, China) for providing us with statistical guidance.