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Japanese Journal of Clinical Oncology Advance Access originally published online on April 24, 2009
Japanese Journal of Clinical Oncology 2009 39(7):418-424; doi:10.1093/jjco/hyp037
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© The Author (2009). Published by Oxford University Press. All rights reserved

NF-{kappa}B Activation Through the Alternative Pathway Correlates with Chemoresistance and Poor Survival in Extranodal NK/T-cell Lymphoma, Nasal Type

Xueguang Liu1,{dagger}, Biyun Wang2,{dagger}, Xuejun Ma3 and Ye Guo2

1 Department of Pathology, Shanghai Medical College, Fudan University
2 Department of Medical Oncology, Cancer Hospital, Shanghai Medical College, Fudan University
3 Department of Radiation Oncology, Cancer Hospital, Shanghai Medical College, Fudan University, Shanghai, China

For reprints and all correspondence: Ye Guo, Department of Medical Oncology, Cancer Hospital of Fudan University, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, China. E-mail: medoncol{at}gmail.com

Received January 11, 2009; accepted March 18, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Objective: Nuclear factor-{kappa}B (NF-{kappa}B) activation has been identified in a variety of solid tumors and lymphoid malignancies. The aim of our study was to determine the expression status and clinical significance of NF-{kappa}B in extranodal natural killer (NK)/T-cell lymphoma, nasal type.

Methods: Tumor specimens from 23 patients with previously untreated NK/T-cell lymphoma initially treated with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) or CHOP-based chemotherapy were examined by immunohistochemistry for three NF-{kappa}B subunits (p65, p50 and p52), which are involved in either the canonical or alternative pathway.

Results: None of the cases could be detected with p65 or p50 nuclear staining. On the other hand, 15 (65.2%) cases had p52 nuclear staining, suggesting NF-{kappa}B activation through the alternative pathway. All major clinical characteristics were balanced between NF-{kappa}B p52-positive and -negative patients. The objective response rate achieved in NF-{kappa}B-positive patients was significantly lower than that in negative patients (33.3% vs. 87.5%, P = 0.027). At a median follow-up of 25 months, 8 (53.3%) of 15 NF-{kappa}B-positive patients had died compared with none of 8 NF-{kappa}B-negative patients (P = 0.041). In a multivariate analysis, NF-{kappa}B status and stage were identified to be independent prognostic factors.

Conclusions: Our results suggest that NF-{kappa}B activation through the alternative pathway is frequently observed in NK/T-cell lymphoma and associated with chemoresistance and poor survival.

Key Words: NK/T-cell lymphoma • NF-{kappa}B • p52 • chemotherapy


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Extranodal natural killer (NK)/T-cell lymphoma, nasal type is an Epstein–Barr virus (EBV)-associated lymphoid malignancy with distinct clinical–pathological features (1). This type of lymphoma is rare in Western populations, but is more common among East Asians and Latin Americans. Nasal cavity is the most common involved site and diagnosis could be confused with chronic rhinitis. In addition, tumor lesion is usually accompanied with inflammation and necrosis, thus increasing the difficulties of precise biopsy and pathological diagnosis.

According to the results of clinical series recently, the prognosis of NK/T-cell lymphoma is quite poor with a 5-year overall survival (OS) of approximately 50% (2–4). Because of the rarity of this disease, vast majority of clinical studies were conducted retrospectively with a limited sample size. Therefore, it is very difficult to compare the clinical outcomes of studies using different treatment modalities. Since most cases with NK/T-cell lymphoma are diagnosed in limited stages (Ann Arbor Stage I or II), combined modalities with chemotherapy and radiotherapy are usually used as the treatment strategy. In contrast with other types of aggressive non-Hodgkin's lymphoma (NHL), patients with NK/T-cell lymphoma are less likely responsive to the doxorubicin-based chemotherapy regimens such as cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) or even dose-intense CHOP (5,6). In a study for patients with limited stage, the complete response (CR) rate of initial chemotherapy was only 25% (7), which was much lower compared with that in patient with other types of diffuse aggressive NHL (8). Although some of the patients without CR could be salvaged by radiotherapy, systemic relapse accounted for half of treatment failure suggesting the ineffectiveness of systemic treatment. Therefore, it is crucial to enhance the systemic treatment either by optimizing the chemotherapy regimens or exploring the novel therapeutic targets.

Nuclear factor-{kappa}B (NF-{kappa}B) transcription factors play an important role in the regulation of immune and inflammatory response (9). NF-{kappa}B is a small family of inducible transcription factors and exists in virtually all mammalian cells. Five NF-{kappa}B subunits, RelA (p65), RelB, c-Rel, p50 and p52, form various homodimers and heterodimers. In resting cell, NF-{kappa}B is sequestered and inactivated in the cytoplasm through interactions with its inhibitory proteins, which comprise I{kappa}B{alpha}, I{kappa}Bβ and I{kappa}B{epsilon}, as well as the p105 and p100 precursors of p50 and p52, respectively. Upon stimulation by a variety of signals, inducible phosphorylation of I{kappa}B by the I{kappa}B kinase (IKK) accounts for its subsequent ubiquitination and proteasome-related degradation resulting in NF-{kappa}B nuclear translocation and transcriptional activation (10). NF-{kappa}B signaling is generally considered to occur through either the canonical or alternative pathway (11). In the canonical pathway, the NF-{kappa}B dimers (most commonly the p50/p65 dimers) are released and translocated to the nucleus with the activation of IKK complex (IKK{alpha}, IKKβ and IKK{gamma}). In the alternative pathway, IKK{alpha} is independently activated for p100 processing to p52 leading to nuclear translocation of p52/RelB dimers. As a result of the activation of either pathway, NF-{kappa}B dimers could induce the expression of various genes regarding cell growth, differentiation, inflammatory responses and the regulation of apoptosis.

Recently, NF-{kappa}B has been related to cancer development and progression (12). NF-{kappa}B was found to be constitutively activated in a variety of solid tumors and lymphoid malignancies (13,14). With regard to NK/T-cell lymphoma, Kim et al. (15) demonstrated the NF-{kappa}B activation in drug-resistance cell lines. In addition, two NF-{kappa}B inhibitors (BAY 11-7082 and curcumin) could suppress NF-{kappa}B activation and induce cell death by enhancing the pro-apoptotic pathway. However, the specific NF-{kappa}B pathway involved was not described in this study. Thus, we were prompted to examine the multiple subunits of NF-{kappa}B protein regarding either the canonical or alternative pathway in vivo.

In the present study, we examined the immunohistochemical expressions of three NF-{kappa}B subunits (p65, p50 and p52) in tumor tissues from patients with previously untreated NK/T-cell lymphoma in attempt to determine the specific NF-{kappa}B pathway. Additionally, we aimed to verify the possible role of NF-{kappa}B as an indicator for chemoresistance and prognosis.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Patient Selection
We previously reported the clinical outcomes of 64 patients with NK/T-cell lymphoma treated in our institution between January 1997 and June 2005 (16). Five patients who received upfront radiotherapy were excluded from this study. Among the remaining 59 patients, 23 patients with adequate paraffin-embedded tumor tissues for immunohistochemical examination were enrolled. Pathological sections of all these cases were reviewed by one of the authors (X.L.) and pathological diagnoses were confirmed in accordance with the WHO criteria. In addition to morphological identification, all tumor cells were positive for CD3, CD45, CD56 and T-cell intracellular antigen-1, but negative for CD20 and CD79a. Positive staining of EBV RNA by in situ hybridization was identified in all cases.

Treatment
All patients with Stages I and II were treated with induction chemotherapy followed by radiotherapy. Chemotherapy alone was the primary treatment for patients with advanced stages and subsequent radiation was performed for local control if complete remission was achieved. Primary chemotherapy consisted of up to six cycles of CHOP or CHOP-based regimens. A minimum of two cycles of chemotherapy was required for all patients. Patients who achieved CR after two or more cycles of chemotherapy were further treated with external beam radiation therapy. Patients who developed local or regional progression during chemotherapy were treated with radiation therapy immediately at the time of progression, and patients who developed distant metastasis during chemotherapy were treated with second-line chemotherapy at the discretion of their attending clinical oncologists. Radiation treatment was delivered by 60Co or linear accelerator with a dose range of between 40 and 50 Gy at 1.8–2.0 Gy/fraction/day, 5 days/week.

Immunohistochemical Study
The antibodies (eBioscience, CA, USA) utilized to detect NF-{kappa}B expression are detailed in Table 1. Immunostaining was done with a routine avidin–biotin–peroxidase complex technique. Briefly, formalin-fixed, paraffin-embedded sections cut at a thickness of 4 µm were deparaffinized and rehydrated through xylenes and a graded alcohol series. Endogenous peroxidase was quenched in 0.6% hydrogen peroxide and antigen retrieval was done by boiling the slides in a microwave for 3 min in citrate buffer (pH 6.0). Non-specific sites were blocked with serum-free protein block for 20 min (Dako, Glostrup, Denmark). The slides were incubated with the primary antibodies at 37°C for 1 h and then at 4°C overnight. Reaction products were developed using 3',3'-diaminobenzidine-tetra-hydrochloride (Dako) as a substrate for peroxidase for 20 min. Sections were counterstained with Meyer's hematoxylin. All of the washes were performed in phosphate-buffered saline (pH 7.4). Reactive tonsil and lymph node tissue sections were used as positive controls. Negative controls were included where the primary antibody was replaced by PBS.


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  		Table 1. Antibodies that were used in the study

 
NF-{kappa}B expression was detected as nuclear and cytoplasmic brown staining of tumor cells. Positive NF-{kappa}B expression, which is regarded as activated NF-{kappa}B, was defined as only distinct nuclear immunostaining in >10% of tumor cells. We selected this cut-off level according to previous NF-{kappa}B immmunohistochemistry studies either for NHL or for gastric cancer (17,18). All stained specimens were independently reviewed by one of the authors (X.L.) without prior knowledge of clinical information.

Data Analysis
Response to treatment was evaluated according to the WHO standard criteria. CR was defined as complete resolution of visible tumor mass on radiology, and partial response (PR) was defined as >50% tumor mass reduction. Stable disease (SD) was defined as a decrease of ≤50% or an increase of ≤25% in tumor size, and progressive disease (PD) was defined as a ≥25% increase in the tumor products of the two diameters, or as the presence of a newly developed lesion. Progression-free survival (PFS) was measured from the start of initial treatment until time of first local or distant progression or relapse, until last follow-up, or death. The duration of OS was calculated from the start of initial treatment until time of death of any causes, or until last follow-up. The PFS and OS rates were calculated by the Kaplan–Meier method and significant differences between the survival rates were determined by the log-rank test. Associations between NF-{kappa}B expression and clinical parameters were assessed by Fisher's exact or {chi}2 test. The Cox's proportional hazard model was used for the multivariate analysis of survival. A P value of <0.05 was considered statistically significant and all P values corresponded to two-sided significant tests.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Patient Characteristics
Table 2 illustrates the patient characteristics. The median age of 23 patients was 46 years (range, 14–79). Based on the Ann Arbor Staging Classification, 16, 5, 1 and 1 patient had Stage I, II, III and IV diseases, respectively. All cases occurred in the nasal cavity as a primary site of tumor. There was a male predominance (15 males and 8 females) and 10 patients had systemic B symptoms. The vast majority of patients (91.3%) had a good performance status (0–1) and normal lactate dehydrogenase (LDH) level before treatment. According to the International Prognosis Index (IPI), 21 patients were classified as low risk (IPI, 0–1), 1 as low-intermediate risk (IPI, 2) and 1 as high-intermediate risk (IPI, 3).


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  		Table 2. Patient characteristics

 
NF-{kappa}B Expression
As shown in Table 3 and Fig. 1(A and B), cytoplasmic stainings for p65 and p50 were observed in 17 (73.9%) and 19 (82.6%) cases, respectively. In contrast, none of cases could be detected with nuclear staining for both NF-{kappa}B subunits. Cytoplasmic and nuclear staining for p52 (Fig. 1C and D) were observed in 7 (30.4%) and 15 (65.2%) cases, respectively. Clinical parameters were investigated for their association with p52 nuclear staining, which was regarded as positive NF-{kappa}B expression (Table 4). There were no correlations between p52 staining status and gender or age of the patients. Moreover, none of the prognostic factors for NHL including stage, performance status, B symptoms, LDH level or IPI correlated with p52 staining status.


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  		Table 3. NF-{kappa}B expression results

 

Figure 1
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  		Figure 1. Immunohistochemical staining of NF-{kappa}B subunits in NK/T-cell lymphoma (x400 magnification). (A) Cytoplasmic staining for p65, (B) cytoplasmic staining for p50, (C) cytoplasmic staining for p52 and (D) nuclear staining for p52.

 

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  		Table 4. Associations between p52 nuclear staining and clinical parameters

 
Response to Chemotherapy
After induction chemotherapy, the objective overall response (OR) rate was 52.2%. Among all 23 patients, 9 patients had CR, 3 had PR, 4 had SD and 7 had PD. When we investigated the OR based on p52 nuclear staining status, p52 expression was significantly associated with resistance to induction chemotherapy. Only five (33.3%) patients with p52-positive staining had an objective response. In contrast, the response rate in patients with negative staining was 87.5% (P = 0.027).

Survival and Multivariate Analysis
At a median follow-up of 25 months, the 2-year PFS and OS rates for all 23 patients were 57% and 61%, respectively. Until this analysis, nine patients relapsed and eight of them died within 1 year. When we compared the survival rates stratified by p52 nuclear staining status, both 2-year PFS and OS rates of p52-positive patients were higher than those of p52-negative patients (PFS: 80% vs. 47%, P = 0.11; OS: 100% vs. 47%, P = 0.041). The PFS and OS curves for two groups are shown in Figs 2 and 3, respectively. Among eight patients without p52 nuclear staining, seven patients were still alive and free of recurrent disease. The remaining patient had a second tumor remission after salvage treatment when his disease relapsed with a PFS of 11 months. In order to confirm the prognostic role of p52 expression, we conducted the multivariate analysis for OS including other potential prognostic factors. As shown in Table 5, p52 nuclear staining was an independent prognostic factor (P = 0.035) and stage was the other one as well (P = 0.01).


Figure 2
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  		Figure 2. Progression-free survival (PFS) stratified by p52 staining status.

 

Figure 3
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  		Figure 3. OS stratified by p52 staining status; OS, overall survival.

 

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  		Table 5. Multivariate analysis for OS

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Conflict of interest statement
 References
 
NF-{kappa}B plays an important role in cancer development and progression. In the past 3 years, various in vivo studies using immunohistochemistry demonstrated that NF-{kappa}B was activated in a variety of cancer types including breast cancer, lung cancer, gastric cancer, esophageal cancer, pancreatic cancer and prostate cancer (19–24). Moreover, NF-{kappa}B activation was universally verified to be an adverse prognostic factor. In the present study for patients with NK/T-cell lymphoma, we observed p52 nuclear staining in 65.2% of cases, whereas none showed p65 or p50 nuclear staining. Since p52 is a key transcription factor involved in the alternative NF-{kappa}B pathway, we selected this surrogate to determine NF-{kappa}B activation and correlated its status with survival. At a median follow-up of 25 months, 8 (53.3%) of 15 NF-{kappa}B-positive patients had died compared with none of 8 NF-{kappa}B-negative patients (P = 0.041). The prognostic role of NF-{kappa}B was confirmed by the subsequent multivariate analysis. Therefore, our results are consistent with previous series aforementioned.

Recently, preliminary data from in vitro studies also suggested the significance of NF-{kappa}B in other types of NHL, such as diffuse large B-cell lymphoma (DLBCL). By the DNA microarray techniques and gene expression profiling, DLBCL could be classified into activated B-cell-like DLBCL (ABC-DLBCL) and germinal center-like DLBCL (GC-DLBCL) with different biology and prognosis (25). Patients with ABC-DLBCL had a significantly poor 5-year survival compared with those with GC-DLBCL (16% vs. 76%, P < 0.01). Davis et al. (26) found that cell lines derived from ABC-DLBCL, but not GC-DLBCL, exhibited constitutive activation of NF-{kappa}B. Furthermore, NF-{kappa}B inhibitors were selectively toxic for ABC-DLBCL cells at nanomolar concentrations (27). These information provided validation of NF-{kappa}B activation as a potential therapeutic target for ABC-DLBCL.

NF-{kappa}B is involved in the regulation of multiple significant signaling pathways including those related to the apoptotic response of cells to injury and cytotoxic treatments. Since most commonly used chemotherapy agents, such as doxorubicin and cisplatin, execute their antineoplastic effect partially based on an intact apoptotic environment, tumor cells conferring high expression of NF-{kappa}B may be resistant to chemotherapy because of NF-{kappa}B-related apoptosis defect (28). In the present study, the objective response rate in NF-{kappa}B-positive patients was significantly lower than that in NF-{kappa}B-negative patients (33.3% vs. 87.5%, P = 0.027). This result is consistent with other series for patients with breast cancer, esophageal cancer and colorectal cancer (29–31). Using different cancer cell lines, several pre-clinical studies showed that NF-{kappa}B inhibition could enhance the efficacy of multiple antineoplastic agents including paclitaxel, etoposide, doxorubicin, cisplatin and irinotecan (32–35). Therefore, it is reasonable to hypothesize that inhibition of NF-{kappa}B or pathways regulated by NF-{kappa}B may be potential targets to overcome the chemoresistance of NK/T-cell lymphoma.

One intriguing finding in our study was the frequent p52 nuclear staining, indicating the activation of the alternative NF-{kappa}B pathway. On the other hand, p65 or p50 expression was observed only in the cytoplasm, suggesting that the canonical pathway was inactivated. The alternative pathway is essential for lymphoid organ development and adaptive immunity (36). Constitutive processing of p100 to p52, due to nfkb2 gene abnormalities, is associated with the development of various hematologic malignancies such as cutaneous T-cell lymphoma, B-cell NHL, chronic lymphocytic leukemia and myeloma. This pathway is usually engaged by a restricted set of cell-surface receptors including lymphotoxin-β receptor, B-cell activating factor receptor and CD40 (37). Recently, strong evidence revealed that p100 processing could be induced by latent member protein 1 (LMP1), which is one of the transforming proteins of EBV (38–40). Since NK/T-cell lymphoma is EBV-associated with Type I/II latency pattern, LMP1 is expressed with variable levels (41). Similarly, p100 processing could be also stimulated by Tax, an oncoprotein transformed by HTLV-1 (human T-cell leukemia virus type 1), which is responsible for adult T-cell lymphoma/leukemia (42). Therefore, there may be a close relation between oncoviral propagation and NF-{kappa}B activation through the alternative pathway.

Although our findings appear to be promising, we recognized three limitations in our study including small sample size, retrospective character and possible selection bias. Fortunately, one prospective Phase II study for NK/T-cell lymphoma in our institution has completed patient accrual and is close to analysis. We plan to confirm our findings and clarify this NF-{kappa}B pathway with more evidence.

In conclusion, our results show that NF-{kappa}B activation through the alternative pathway is frequent in extranodal NK/T-cell lymphoma, nasal type. Additionally, NF-{kappa}B status significantly correlates with chemotherapy response and survival. Since NF-{kappa}B is valuable as either a predictive factor or a prognostic factor, it appears to be a potential therapeutic target for NK/T-cell lymphoma. More studies are warranted to further investigate the NF-{kappa}B pathway and clarify the mechanism of NF-{kappa}B activation.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Conflict of interest statement
 References
 
This work was supported by translational research fund from Shanghai Medical College of Fudan University (JC08-20).


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
References
 
None declared.


   Footnotes
 
{dagger} These authors contributed equally to this work. Back


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
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