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Clinical Cancer Research Vol. 12, 5112-5117, September 1, 2006
© 2006 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Overexpression of Hypoxia-Inducible Factor 1{alpha} and p53 Is a Marker for an Unfavorable Prognosis in Gastric Cancer

Yasushi Sumiyoshi1, Yoshihiro Kakeji1, Akinori Egashira1, Ken Mizokami1, Hiroyuki Orita2 and Yoshihiko Maehara1

Authors' Affiliations: 1 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka and 2 Department of Surgery, Saga Prefectural Hospital Koseikan, Saga, Japan

Requests for reprints: Yoshihiro Kakeji, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-5466; Fax: 81-92-642-5482; E-mail: kakeji{at}surg2.med.kyushu-u.ac.jp.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: To investigate the effects of the expression of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) and p53 on the prognosis of human gastric cancer, the clinicopathologic characteristics of the tumors and the clinical outcome were analyzed.

Experimental Design: The expressions of HIF-1{alpha} and p53 proteins were studied by immunohistochemistry in 216 specimens of primary gastric cancer.

Results: HIF-1{alpha}(+)/p53(+) tumors more frequently showed an undifferentiated type, an infiltrative growth appearance, and an invasive lymphatic involvement compared with HIF-1{alpha}(–)/p53(–) tumors. HIF-1{alpha}(+)/p53(+) tumors also had more lymph node metastasis compared with HIF-1{alpha}(–)/p53(–) tumors. When stratified for HIF-1{alpha} and p53 positivity, the patients who were p53-negative and HIF-1{alpha}-negative had the most favorable prognosis, whereas patients who were p53-positive and HIF-1{alpha}-positive had the worst prognosis (P = 0.0018). Using a multivariate Cox regression analysis, the depth of invasion, lymph node metastasis, and HIF-1{alpha} positivity were all found to be independent prognostic factors in patients with gastric cancer.

Conclusion: Thus, HIF-1{alpha} is considered to be a useful independent prognostic factor in gastric cancer, and the combination of a HIF-1{alpha} protein overexpression with nonfunctional p53 tends to indicate a dismal prognosis.

In the absence of neovascularization, the growth of malignant epithelial tumors is limited to several cubic millimeters because of the restricted capacities of oxygen and/or glucose diffusion from blood vessels (1). Oxygen concentrations are gradually decreasing from the normoxic perivascular regions of proliferating cells, across the hypoxic layers of resting cells, reaching anoxic conditions in the necrotic centers (2). Hypoxia limits tumor growth, and tumors with poor vascularization fail to grow and form metastases (3). However, hypoxia also positively affects tumor growth by inducing cellular adaptations (e.g., anaerobic glycolysis) as well as local (e.g., angiogenesis) and genetic (e.g., p53 mutation) alterations (4). Hypoxia induces the expression of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}), which then mediates a series of transcriptional responses (5). The cognate DNA recognition site of HIF-1{alpha} is the hypoxia response element (6, 7). HIF-1{alpha} binds to the hypoxia response element of the target genes, such as vascular endothelial growth factor (VEGF), erythropoietin, and glycolytic enzymes. Hypoxia/anoxia has also been reported to induce wild-type p53 by a different pathway than DNA-damaging agents (8). The hypoxic/anoxic induction of p53 selects for tumor cells lacking functional p53, and hence, displaying a diminished apoptotic potential (9). Moreover, p53 mutation has proangiogenic effects because wild-type p53 induces thrombospondin-1, a potent inhibitor of angiogenesis (10), and it may or may not inhibit VEGF expression (11, 12). The interaction of HIF-1{alpha} and p53, which affects tumor growth and the clinical outcome of patients, is still obscure to some extent.

The overexpression of HIF-1{alpha} and p53 protein has been shown in a variety of human cancers using immunohistochemistry (13, 14); no data regarding their effects on prognosis, in particular, in gastric cancer, have yet been reported. The aim of our study was to investigate the effects of HIF-1{alpha} and p53 expression on the prognosis in human gastric cancer.


   Materials and Methods
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Patients studied. This study included 216 unselected Japanese patients with primary gastric cancer, all of whom underwent gastrectomy between 1992 and 1995 at the Department of Surgery and Science (Surgery II), Kyushu University Hospital, Fukuoka or at the Department of Surgery, Saga Prefectural Hospital Koseikan, Saga, Japan. They included 148 men and 68 women, ranging from 27 to 88 years of age (mean, 65.2 years). A thorough histologic examination was made using H&E-stained tissue preparations, and the histologic classification was made according to the general rules set up by the Japanese Research Society for Gastric Cancer (15). No patient treated preoperatively with cytotoxic drugs was included in this study.

Immunohistochemical staining of HIF-1{alpha} and p53. The avidin-biotin complex method was used for HIF-1{alpha} immunohistochemical staining. Tumor specimens were collected and fixed in 10% formalin. One paraffin block contained both cancerous and adjacent noncancerous tissue, and cancerous tissue invading the deepest area of the stomach wall was selected in all cases. Sections 5-µm-thick from paraffin-embedded blocks were deparaffinized in xylene and rehydrated in a graded series of ethanols. After quenching the endogenous peroxidase activity in methanol containing 0.3% (v/v) hydrogen peroxidase for 10 minutes, the sections were incubated with 10% normal rabbit serum to block any nonspecific binding of the immunoreagents. NB 100-105 (Novus Biologicals, Littleton, CO) is a monoclonal antibody (IgG2b, clone Mab H1{alpha} 67) against HIF-1{alpha} (13). The sections were incubated for 2 hours at room temperature with NB 100-105 at a 1:100 dilution. A Histofine SAB-PO (M) kit (Nichirei Corp., Tokyo, Japan) was used after three washes with PBS. The sections were then incubated with biotinylated rabbit anti-mouse immunoglobulin (IgG, IgA, and IgM; Nichirei) for 10 minutes followed by three washes in PBS. The slides were treated with peroxidase-conjugated streptoavidin for 10 minutes. After washing in PBS, peroxidase labeling was developed by incubating the sections in diaminobenzidine tetrahydrochloride for 3 minutes. Finally, nuclear counterstaining was done using Mayer's hematoxylin solution. The specificity of binding for antibody was examined using nonimmune sera instead of a specific antibody. Automated immunohistochemistry was also done to support the immunostaining described above, using a Ventana Discovery System (Ventana Medical Systems, Inc., Tucson, AZ).

A positive value was recorded if there was nuclear staining in >10% of the tumor cells; concomitant cytoplasmic staining was not counted (16) because HIF-1{alpha} protein in the nucleus determines the functional activity of the HIF-1{alpha} complex (7).

The expression of p53 was investigated using a monoclonal antibody against p53 (PAb1801; Oncogene Science, Cambridge, MA; ref. 16). The specimens were then incubated for 1 hour with a 1:50 dilution of primary antibody at room temperature. When 10% of the cancer cells showed positive nuclear staining, then positive staining was defined (17).

Cells were considered immunoreactive to HIF-1{alpha} when distinct nuclear staining was identified, as previously described (13). Appropriate gastric cancer tissues were used as a positive control for p53 antibody (18). Negative controls were obtained by replacing the primary antibody with nonimmune serum.

Immunohistochemical staining of VEGF and microvessel density. The primary antibody, A-20 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), was used. The sections were incubated for 2 hours with A-20 (1:50 dilution) at room temperature. The positive rate of VEGF staining was determined by counting the number of tumor cells in which the cytoplasm was stained with antibodies. For evaluation, 10 fields at the invasive front were selected and a total of 1,000 tumor cells (100 for each field) were counted microscopically under high power (x200). The degree of polyclonal antibody reactivity with the individual tissue sections was considered to be positive if unequivocal staining of the membrane or the cytoplasm was in >5% of tumor cells, as previously described (19).

A procedure for detecting microvessels and an anti-CD34 monoclonal antibody were used (Dako, Glostrup, Denmark). An evaluation of microvessel density was determined, using the modified technique of Weidner et al. (20). All slides were scanned at a low magnification (x40 or x100), and the area of the most dense neovascularization (greatest number of capillaries or small venules) was determined. Individual microvessel counts were made on a x200 field (0.739 mm2 per field). Positive cells or cell clusters, clearly separate from the adjacent microvessels, tumor cells, and other connective tissue elements, were considered to be a single, countable microvessel. The distribution of the most intense area of vascularization was heterogeneous in each tumor. In all samples, the mean value for the number of microvessels was calculated from five highly vascularized areas of "hotspots."

All evaluations for immunostainings were done by two independent observers (Y. Sumiyoshi and Y. Kakeji) without any knowledge of the patient's clinical status. A double-headed light microscope was used.

Statistical analysis. The clinicopathologic data were stored in an IBM 3090 mainframe computer (IBM, Armonk, NY). The Biomedical Computer Program (BMDP) was used for all statistical analyses (21). The BMDP P4F and P3S programs were used for the {chi}2 test and the Mann-Whitney test to compare the characteristics between groups. The BMDP P1L program was used for the Kaplan-Meier analysis of the survival rates and the Mantel-Cox test was used to analyze the equality of the survival curves. The BMDP P2L program was used for the simultaneous multivariate adjustments of all covariates using Cox regression analysis (22).


   Results
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Discussion
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HIF-1{alpha} and p53 immunostaining. The patterns of HIF-1{alpha} expression in the tumor cells were mixed nuclear/cytoplasmic staining. There was no expression of this protein in the normal epithelium in this study. HIF-1{alpha} expression through nuclear staining of positive cells was predominant at the invading edge of the tumor margin and at the periphery of necrotic regions within tumors (Fig. 1A ). Of all 216 patients, 85 (39.4%) showed positive findings for HIF-1{alpha} immunoreactivity.


Figure 1
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  		Fig. 1. A, the nuclear staining of HIF-1{alpha} around the necrotic region in gastric cancer (magnification, x400). B, p53 staining of the nucleus of cancer cells (magnification, x400).

 
On the other hand, even though a distinct nuclear immunoreaction for p53 was recorded as positive, the nuclear staining pattern was diffuse with little variation (Fig. 1B). The positive rate of p53 overexpression in gastric cancer cells was 47.2% (102 of 216). The staining of p53 was nuclear, and p53 was never observed in the cytoplasm of any of the 216 cases.

Clinicopathologic characteristics. Table 1 shows the clinicopathologic features and HIF-1{alpha}/p53 expression in patients with gastric cancer. HIF-1{alpha}(+)/p53(+) tumors were more frequently of the undifferentiated type, infiltrative growth pattern, invasive in lymphatic involvement compared with HIF-1{alpha}(–)/p53(–) tumors. HIF-1{alpha}(+)/p53(+) tumors also had more lymph node metastasis compared with HIF-1{alpha}(–)/p53(–) tumors.


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  		Table 1. p53/HIF-1{alpha} expression and clinicopathologic factors in patients with gastric cancer

 
Intratumoral angiogenesis. Figure 2 shows the VEGF-positive rates and microvessel density in the subgroups of HIF-1{alpha}/p53 stainability. The HIF-1{alpha}(+)/p53(+) tumors had a significantly higher VEGF-positive rate and microvessel density compared with the HIF-1{alpha}(–)/p53(–) tumors (P < 0.05 and P < 0.01, respectively).


Figure 2
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  		Fig. 2. VEGF-positive rates and microvessel density in the subgroups of HIF-1{alpha}/p53 stainability. Columns, mean of VEGF-positive rates; bars, microvessel density (±SD).

 
Prognosis. Figure 3A shows the survival curves of the patients according to positive or negative HIF-1{alpha} staining. Patients with positive HIF-1{alpha} cancers showed lower survival rates than patients with negative HIF-1{alpha} cancers (P = 0.0015). The postoperative survival curves for patients with p53-negative and p53-positive tumors are shown in Fig. 3B. The survival time was shorter for patients with p53-positive compared with p53-negative tumors, and the difference was statistically significant (P = 0.0353). When stratified for HIF-1{alpha}-negative and HIF-1{alpha}-positive patients in the p53-negative and p53-positive subgroups, a statistical difference was observed among the groups (Fig. 3C). The p53-negative and HIF-1{alpha}-negative patients had the most favorable prognosis, whereas the p53-positive and HIF-1{alpha}-positive patients had the worst prognosis (P = 0.0018).


Figure 3
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  		Fig. 3. Survival curves for patients with gastric cancer, in relation to HIF-1{alpha} and p53 expressions. A, patients with HIF-1{alpha}-positive tumors (n = 85) had a shorter survival time than did those with HIF-1{alpha}-negative tumors (n = 131, P = 0.0015). B, patients with p53-positive tumors (n = 102) had a shorter survival time than did those with p53-negative tumors (n = 114, P = 0.0353). C, there was a significant difference among groups stratified to HIF-1{alpha}/p53 expressions (P = 0.0018). The patients with HIF-1{alpha}(+)/p53(+) tumors had the worst prognosis.

 
To search for an independent prognostic factor, we carried out a multivariate Cox regression analysis (Table 2 ). The factors examined included sex, age, tumor size, histologic growth pattern, histologic type, depth of invasion, lymphatic invasion, vessel invasion, lymph node metastasis, peritoneal dissemination, liver metastasis, HIF-1{alpha}, VEGF, and p53 expression. Based on the above findings, in patients with gastric cancer, lymph node metastasis, the depth of invasion, liver metastasis, peritoneal dissemination, and HIF-1{alpha} positivity were all found to be independent prognostic factors.


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  		Table 2. Cox regression analysis for patients with gastric cancer (n = 216)

 

   Discussion
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HIF-1{alpha} has been shown as a key molecule, which is related to proliferation and angiogenesis in various malignancies. Regarding the gastrointestinal tumor, there are two reports showing that the expression of HIF-1{alpha} in gastrointestinal stromal tumor is a feature of adverse prognosis (23, 24). Furthermore, inhibition of HIF-1{alpha} activity impairs gastric tumor growth, angiogenesis, and vessel maturation in vitro (25). However, thus far, there are no published studies correlating HIF-1{alpha} expression with prognosis in gastric adenocarcinoma (26). A large study is required to investigate the HIF-1{alpha} expression in gastric carcinoma and to determine its value in predicting the outcome. In this study, a multivariate Cox regression analysis showed HIF-1{alpha} to be one of the independent prognostic factors in gastric cancer. Our previous study showed a correlation between the HIF-1{alpha} overexpression and the induction of angiogenesis in gastric cancer by a semiquantitative assessment of the formation of blood vessels.3 This finding can be explained by the notion that angiogenesis was promoted by the HIF-1{alpha}-induced expression of VEGF (27).

When the cells are exposed to hypoxia or growth factors, HIF-1{alpha} accumulates within the nucleus, dimerizes with HIF-1ß, binds to the target genes in a sequence-specific manner, and activates their transcription (28). In addition to the role of HIF-1 as a DNA-binding protein, HIF-1{alpha} has also been shown to exert biological effects via protein-protein interactions. Under hypoxic conditions, HIF-1{alpha} has been shown to interact with the tumor suppressor protein p53, which itself is a DNA-binding transcription factor. This interaction seems to increase the half-life of p53 (29) and decrease the half-life of HIF-1{alpha} as a result of an increased ubiquitination by MDM2, a ubiquitin protein ligase that binds to p53 (30). The HIF-1{alpha}-mediated stabilization of p53 may contribute to hypoxia-mediated apoptosis, which may in turn, represent a critical selective force for p53 loss of function (9). The alternative explanation is that tumors with stainable p53 have a defect in the p53-dependent apoptotic pathway in addition to overexpressing HIF.

The loss of p53 activity also promotes angiogenesis by increasing the expression of the angiogenic factor VEGF (30). The vessel counts and VEGF expression are higher in the colon cancers that express mutant p53 (31). The ubiquitination of HIF-1{alpha} is reduced in p53–/– cells, whereas transfection with a p53 expression vector is associated with increased ubiquitination (30). MDM2 coimmunoprecipitates with p53 and HIF-1{alpha}, and mutant forms of p53 that cannot interact with MDM2 do not affect HIF-1{alpha} expression. Finally, in p53+/+ cells, the expression of mutant forms of MDM2 that can bind to p53, but are deficient in ubiquitin-protein ligase activity, result in increased HIF-1{alpha} protein levels (30). The preferential ubiquitination of HIF-1{alpha} by MDM2 in the trimolecular complex may account for the HIF-1{alpha}-mediated stabilization of p53 as described above. Most importantly, these data suggest that the loss of p53 activity not only protects tumor cells from hypoxia-mediated apoptosis, but also promotes metabolic adaptation and angiogenesis as a result of an increased HIF-1 activity (32). Schmid et al. (33) reviewed the recent information on the accumulation of HIF-1{alpha} and p53 under hypoxia and thus provided a model to explain the communication between HIF-1 and p53 under physiologic conditions. p53 accumulates to a relevant degree only under drastic conditions of oxygen depletion; subsequently, it represses HIF-1 activity and eventually destabilizes HIF-1{alpha} (34). Regarding the mechanism of action, the interaction between HIF-1{alpha} and p53 is proposed to be either direct (35) or indirect via Mdm2 (36), and that conditions of hypoxia/anoxia that resulted in p53 stabilization and its transcriptional activation have been observed to concomitantly promote HIF-1{alpha} degradation (34).

Herein, we show for the first time that the expression of HIF-1{alpha}, in combination with nonfunctional p53 protein, indicates a dismal prognosis in gastric cancer. In ovarian tumors, p53 protein overexpression, in addition to HIF-1{alpha} expression, increased the overall survival rate (37). More recently, it was reported that HIF-1{alpha} expression influenced progression-free survival, and that the combination of p53 and HIF-1{alpha} overexpression was statistically important for superficial urothelial carcinoma (38). The explanation for this phenomenon might be that the dual function of HIF-1{alpha} in early carcinogenesis which, on one hand, stimulates tumor progression, whereas on the other hand, it supports the apoptosis of tumor cells. A correlation between HIF-1{alpha} and the apoptotic rate of tumor cells has previously been observed in lung cancer (39) and ovarian cancer (40). However, this proapoptotic function of HIF-1{alpha} seems to get lost in cancers with nonfunctional p53. Hypoxic cancer cells with a low apoptotic index have been reported to be highly aggressive (40). The combination of p53 protein dysfunction, e.g., through somatic mutation, and HIF-1{alpha} overexpression seems to be necessary to allow HIF-1{alpha} to sufficiently stimulate tumor progression in early carcinogenesis by mediating angiogenesis and by inducing adaptive intracellular responses to hypoxia without supporting any proapoptotic mechanisms (37).

In conclusion, HIF-1{alpha} protein overexpression alone is thus considered to influence the prognosis of patients with gastric cancer because of neoangiogenesis. In combination with an overexpression of p53 protein, HIF-1{alpha} protein overexpression therefore tends to indicate a dismal prognosis.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

3 K. Mizokami, Y. Kakeji, S. Oda, K. Irie, T. Yonemura, Y. Maehara. Growth of gastric cancer is related to angiogenesis with the expression of hypoxia-inducible factor 1{alpha}. J Surg Oncol 2006;94:149–54. Back

Received 11/ 2/05; revised 1/27/06; accepted 3/ 3/06.


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Commentary

Hypoxia-Inducible Factor-1 and p53: Friends, Acquaintances, or Strangers?
Ester M. Hammond and Amato J. Giaccia
Clin. Cancer Res. 2006 12: 5007-5009. [Full Text] [PDF]



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E. M. Hammond and A. J. Giaccia
Hypoxia-Inducible Factor-1 and p53: Friends, Acquaintances, or Strangers?
Clin. Cancer Res., September 1, 2006; 12(17): 5007 - 5009.
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