Abstract
Pancreatic cancer (PC) is an aggressive and devastating disease with a dismal prognosis. The study aimed to investigate the role of HSP90α and PDIA3 in patients with PC. Immunohistochemistry was performed on tissue microarrays containing 186 pairs of PC and normal pancreatic tissues to assess the expression levels of HSP90α and PDIA3. The expression levels of cytoplasmic HSP90α (P = 0.032) and PDIA3 (P = 0.043) in PCs were significantly higher than those in normal pancreas tissues, but nuclear HSP90α showed lower expression in PC tissues (P = 0.002). In addition, cytoplasmic expression of HSP90α and PDIA3 was significantly associated with perineural invasion (PNI) (P = 0.004) and sex (P = 0.014), respectively. These results indicate that cytoplasmic HSP90α may serve as a biomarker for PNI in PCs.
Keywords: Pancreatic cancer, HSP90α, PDIA3, perineural invasion
Introduction
Pancreatic cancer (PC) is an aggressive and devastating disease with a dismal prognosis. It is predicted that approximately 46,420 new PC cases and 39,590 deaths from PC will occur in the United States in 2014 [1]. With the combination of earlier diagnosis and improvements in cancer treatment, survival rates for some types of cancer have been increasing during the last few decades. However, PC remains one of cancers that have shown little improvement in survival over the past 30 years. Moreover, PC is less sensitive to chemotherapy [2]. The majority of PC are not diagnosed until its late stages due to lack of early detection tests and recognizable symptoms or signs for patients with localized PC. Therefore, identification of novel biomarkers, which can target tumors’ occurrence, development and metastasis, is the key to preventing and curing of PC.
Heat shock proteins (HSP), highly conserved proteins, act as molecular chaperones for cellular proteins and are essential for normal cell viability and growth. HSPs are up-regulated in a wide range of tumors [3]. Mammalian HSPs have been classified mainly in four families according to their molecular weight: HSP90, HSP70, HSP60 and small HSPs (15-30 kDa). There are two HSP90 isoforms, HSP90α and HSP90β, encoded by the HSP90AA1 and HSP90AB1 genes, respectively [4]. HSP90 is an important therapeutic target for cancer treatment since its clients include oncoproteins with important functions in the development and progression of cancer, indicated that inhibition of Hsp90 may represent an attractive therapeutic strategy for cancer [5-7]. However, the use of HSP90 as a biomarker of pancreatic cancer has not been reported.
Protein disulfide isomerase (PDI) is a protein of the endoplasmic reticulum where it assists redox protein-folding involving oxidation and multiple intramolecular thiol-disulfide exchanges [8]. As a member of the PDI family and of the thioredoxin (Trx) superfamily, protein disulfide-isomerase A3 precursor (PDIA3) is associated with many diseases including colon cancer, ovarian cancer and von Willebrand’s disease [9-11]. Moreover, lack of PDIA3 expression also correlates with increased tumor invasion and advanced stage of gastric cancer and has therefore been proposed to be a negative prognostic biomarker [12].
Our previous study has shown that both HSP90AA1 and PDIA3 are differentially expressed in PC tissues [13]. Therefore, in the present study, we investigated the expression levels of HSP90α and PDIA3 in 169 PC tissues, and examined the relationship between the expression of HSP90α and PDIA3 and clinical features of PC patients.
Materials and methods
Patients
Tumor tissue samples were collected from 186 patients who underwent cancer surgical resection, and the samples were stored at the Biobank Center in National Engineering Center for Biochip at Shanghai. All patients were histologically diagnosed with PC. The degree of perineural invasion (PNI) was classified into four grades [14]: Ne0-no perineural invasion; Ne1-neurium invasion; Ne2-perineural space invasion; Ne3-nerve bundle invasion. Written informed consent was obtained from all patients, and the protocol was approved by the Ethical Committee of National Engineering Center for Biochip at Shanghai.
Tissue microarray construction (TMA)
PC tissue microarrays were constructed using tissue cores from formalin-fixed, paraffin-embedded specimens as previously described [15]. Representative cancer regions and paracancerous nonmalignant pancreatic specimens were selected by pathologists from each tissue block, and a single 0.6 mm core was taken from every donor block. Microarray blocks were constructed using an automated tissue arrayer (Beecher Instruments, Sun Prarie, WI). Five-micron sections were cut from the array blocks. In all cases, cores were also from taken normal adjacent pancreas for use as internal controls. Sections were then stained with H&E to confirm the presence of tumor within each core.
Immunohistochemistry and scoring
The IHC staining was performed using TMA slides that were deparaffinized in xylene, rehydrated through a graded alcohol series, washed with Tris-buffered saline, and processed using a streptavidin-biotin-peroxidase complex method. For antigen retrieval, TMA slides were boiled by a pressure cooker in 10 mM sodium citrate buffer (pH 6) for 10 min. After quenching of endogenous peroxidase activity and blocking of nonspecific binding, HSP90α and PDIA3 antibodies were added at a special dilution, 1:8000 and 1:200 respectively, and then slides were incubated with primary antibody overnight in a humid chamber at 4°C. The corresponding secondary biotinylated rabbit antibody was used at a special dilution for 30 minutes at room temperature. After further washing with Tris-buffered saline, sections were incubated with StrepAB Complex/horseradish peroxidase (1:100, DAKO) for 30 minutes at room temperature. Chromogenic immunolocalization was performed using 0.05% 3,3-diaminobenzidine tetrahydrochloride. Slides were counterstained with diluted hematoxylin before dehydration and mounting. Other cores containing pancreatic cancer served as positive controls for those genes expression. Normal serum was used in the place of primary antibody as a negative control.
The slides stained by IHC were assessed by two pathologists who were blinded to clinical information. The staining intensity of cancer cells was scored as [16]: 0, negative; 1, weak; 2, moderate; 3, strong staining. For statistical evaluation, tumors were scored as 0, non-staining; 1, 1-20%; 2, 21-75%; 3, 76-100% positive cells. The total histological score, which was the result of multiplication of intensity and percentage scores, was utilized to determine the result. The total histological score < 4 indicated as a low level of expression, whereas a total histological score ≥ 4 denotes a high level of expression [17]. In cases of disagreement, a consensus was reached by joint review.
Statistical analysis
All statistical analyses were performed using SPSS v20.0 software (SPSS, Inc., Chicago, IL). The difference in the expression levels of HSP90α and PDIA3 between PC and adjacent normal tissues was analyzed using Mann-Whitney test. All patients were divided into two groups, high and low expression, according to the median expression levels of HSP90α and PDIA3, respectively. The relationships between the expression levels of HSP90α and PDIA3, and clinicopathological parameters of patients were analyzed using the Chi-square test. Spearman test was applied to evaluate correlation between HSP90α cytoplasmic expression and PDIA3 cytoplasmic expression. Statistical significance was determined by a two-tailed with P value < 0.05.
Results
Clinicopathological characteristic of PC patients
The characteristics of PC patients enrolled in this study were summarized in Table 1. Among 186 PC patients, 117 are male (61.8%) and 71 are females (38.2%). The median age was 61 year (range 30-86 years). The most frequent location of PC was in the head (136 cases, 73.1%) followed by the body or tail (48 cases, 25.8%) of the pancreas. One hundred and thirty-five (71%) are highly or moderately differentiated, and 32 (17.2%) were poorly differentiated. The tumor size ranged from 1 cm to 14 cm, with the median size of 5.27 cm as the median. One hundred and thirty four (72%) had no regional lymph node metastasis (LNM), whereas 34 (18.3%) had regional lymph node metastasis. PNI was observed in 99 cases (53.2%).
Table 1.
Clinicopathological characteristic of PC patients
| Characteristics | No. | % |
|---|---|---|
| Age (year) | ||
| Median | 61 | |
| range | 30-86 | |
| Sex | ||
| female | 71 | 38.2 |
| male | 115 | 61.8 |
| Location | ||
| head | 136 | 73.1 |
| body/rear | 48 | 25.8 |
| unknown | 2 | 1.1 |
| Histologic grade | ||
| 1 | 19 | 10.2 |
| 2 | 113 | 60.8 |
| 3 | 32 | 17.2 |
| unknown | 22 | 11.8 |
| Tumor size (cm) | ||
| median | 5.27 | |
| range | 1-14 | |
| LNM | ||
| positive | 34 | 18.3 |
| negative | 134 | 72 |
| unknown | 18 | 9.7 |
| PNI | ||
| Ne0 | 87 | 46.8 |
| Ne1 | 79 | 42.5 |
| Ne2 | 16 | 8.6 |
| Ne3 | 4 | 2.2 |
Expression of HSP90α and PDIA3 in PC and normal pancreas tissues
HSP90α was localized to the cytoplasm and the nucleus of both PC and pancreas cells, but PDIA3 staining was mainly localized to the cytoplasm and nuclear PDIA3 expression was relatively rare (Figure 1). PC showed higher expression of cytoplasmic HSP90α (P = 0.032) and PDIA3 (P = 0.043) than normal pancreas tissues, but nuclear HSP90α showed a lower expression in PC tissues (P = 0.002). One hundred and twenty-three (66.1%) PCs showed strong positive cytoplasmic staining for HSP90α, whereas only 49 (26.3%) PCs showed strong positive nuclear staining for HSP90α. Strong cytoplasmic expression of PDIA3 was observed in 66.7% (124/186) of PCs. Furthermore, cytoplasmic HSP90α expression was significantly correlated with cytoplasmic PDIA3 expression (Spearman correlation coefficient of 0.337, P < 0.001).
Figure 1.
Immunohistochemical staining of HSP90α and PDIA3 in PC and normal pancreas tissues. A: The expression of HSP90α in pancreatic tissues. B: The expression of HSP90α in PCs. C: The expression of PDIA3 in pancreatic tissues. D: The expression of PDIA3 in PCs. All images were taken at 200× magnification.
Relationships between the expression of HSP90α and PDIA3 and clinicopathological features of PC patients
In order to investigate the relationships between expression of HSP90α and PDIA3 and clinicopathological features of PC, the following information of each patient was chosen: sex, age, tumor location, tumor size, LNM, PNI and histologic grade. Cytoplasmic PDIA3 expression was significantly associated with sex (P = 0.016), while cytoplasmic HSP90α expression was significantly associated with PNI (P = 0.004). No other significant difference was observed between expression of HSP90α and PDIA3 and clinicopathological features (Table 2).
Table 2.
Relationships between expression of HSP90α and PDIA3 and clinicopathological features of PC patients
| Clinical features | Cytoplasmic HSP90α expression | Nuclear HSP90α expression | Cytoplasmic PDIA3 expression | ||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| High | Low | P value | High | Low | P value | High | Low | P value | |
|
|
|
|
|||||||
| N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | ||||
| Age (years) | |||||||||
| ≤ 60 | 57 (46.3) | 26 (41.9) | 0.570 | 19 (38.8) | 64 (47.1) | 0.318 | 56 (45.5) | 27 (43.5) | 0.798 |
| > 60 | 66 (53.7) | 36 (58.1) | 30 (61.2) | 72 (52.9) | 67 (54.5) | 35 (56.5) | |||
| Sex | |||||||||
| male | 74 (60.2) | 41 (65.1) | 0.427 | 29 (59.2) | 86 (62.8) | 0.657 | 69 (55.6) | 46 (74.2) | 0.016 |
| female | 49 (39.8) | 22 (34.9) | 20 (40.8) | 51 (37.2) | 55 (44.4) | 16 (25.8) | |||
| Location | |||||||||
| Head | 92 (76.0) | 44 (69.8) | 0.364 | 35 (74.5) | 101 (73.7) | 0.920 | 88 (72.1) | 48 (77.4) | 0.440 |
| Body/rear | 29 (24.0) | 19 (30.2) | 12 (25.5) | 36 (26.3) | 34 (27.9) | 14 (22.6) | |||
| Histologic grade | |||||||||
| 1 | 13 (11.8) | 6 (11.1) | 0.976 | 3 (7.0) | 16 (13.2) | 0.335 | 11 (10.2) | 8 (14.3) | 0.589 |
| 2 | 76 (69.1) | 37 (68.5) | 29 (67.4) | 84 (69.4) | 74 (68.5) | 39 (69.6) | |||
| 3 | 21 (19.1) | 11 (20.4) | 11 (25.6) | 21 (17.4) | 23 (21.3) | 9 (16.1) | |||
| Tumor size (cm) | |||||||||
| ≤ 4 | 47 (42.7) | 19 (42.2) | 0.954 | 18 (46.2) | 48 (41.4) | 0.602 | 48 (47.5) | 18 (33.3) | 0.125 |
| > 4 | 63 (57.3) | 26 (57.8) | 21 (53.8) | 68 (58.6) | 53 (52.5) | 36 (66.7) | |||
| LNM | |||||||||
| Positive | 20 (17.5) | 14 (25.9) | 0.207 | 8 (16.7) | 26 (21.7) | 0.466 | 26 (23.0) | 8 (14.5) | 0.226 |
| Negative | 94 (82.5) | 40 (74.1) | 40 (83.3) | 94 (78.3) | 87 (77.0) | 47 (85.5) | |||
| PNI | |||||||||
| Ne0 | 55 (44.7) | 32 (50.8) | 0.004 | 20 (40.8) | 67 (48.9) | 0.756 | 55 (44.4) | 32 (51.6) | 0.338 |
| Ne1 | 61 (49.6) | 18 (28.6) | 24 (49.0) | 55 (40.1) | 58 (46.8) | 21 (33.9) | |||
| Ne2 | 6 (4.9) | 10 (15.8) | 4 (8.2) | 12 (8.8) | 9 (7.3) | 7 (11.3) | |||
| Ne3 | 1 (0.8) | 3 (4.8) | 1 (2.0) | 3 (2.2) | 2 (3.2) | ||||
Discussion
HSP90 overexpression has been observed in a wide range of human cancers including gastric, breast, endometrial, ovarian, colon, lung and prostate cancers [18-21]. Inhibition of HSP90 leads to the degradation and inactivation of many HSP90 client proteins, including several oncogenic proteins [22]. Recently, HSP90 inhibitors, such as geldanamycin derivatives, have shown promising antitumor activity in preclinical studies and are currently undergoing clinical trials for the treatment of several cancers, including breast [23,24], lung [24], pancreatic [25] and prostate cancers [26]. In case of PC, 17-allylamino-17-demethoxygeldanamycin (17-AAG) suppresses growth and induces apoptosis in human PC cells through inhibition of multiple kinases [27]. Ogata et al. [28] reported that a higher level of HSP90 expression was shown in poorly differentiated PCs than in well to moderately PCs and HSP90α was upregulated in PCs. In the present study, we also found that the expression level of HSP90α was increased in PCs, suggesting oncogenic function of HSP90α in the carcinogenesis pancreatic cancer.
PNI is defined as the presence of cancer cells along nerves and/or within the epineurial, perineurial, and endoneurial spaces of the neuronal sheath [14]. Because of the special anatomy structure, PC patients has high incidence of PNI. PNI is thought to be an indicator of aggressive tumour behavior and has been shown to correlate with poor prognosis of PC patients [29]. Previous studies have proved this process involves many different signaling pathways and many signaling molecules from these pathways between the cancer cells and peripheral nerves [14,30]. HSP90 is a molecular chaperone that aids protein folding and quality control for a large number of client proteins [31]. Cancer cell metabolism and signal transduction pathways are activated by HSP90 and the stability of various oncogenic factors is almost entirely dependent on HSP90 binding [32]. HSP90α promotes colorectal cancer cell migration and invasion by inducing TCF12 expression to down-regulate E-cadherin [33]. In this study, we also found that the level of HSP90α was higher in PNI positive PCs compared with non-PNI PCs. These findings indicate that upregulation of HSP90α is linked to invasiveness in PC and provide support for the potential use of HSP90 inhibitors as an adjunctive therapeutic agent in the treatment of invasive PC.
In conclusion, we found that HSP90α and PDIA3 were up-regulated in PCs and cytoplasmic HSP90α expression was associated with PNI. Cytoplasmic HSP90α may serve as a biomarker for PNI in PCs. However, further studies are required to elucidate the mechanism underlying invasion in PC.
Acknowledgements
This work was supported by the Science Technology Development Fund of Shanghai Pudong New District, China (PKJ2011-Y12), the 12th Five-Year Plan Key Project of Science and Technology, China (grant No. 2013ZX10002007), the Shanghai Committee of Science and Technology, China (grant No. 13440701500), and the Jiangsu Province Science and Technology Support Program, China (grant No. BE2012729).
Disclosure of conflict of interest
None.
References
- 1.Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29. doi: 10.3322/caac.21208. [DOI] [PubMed] [Google Scholar]
- 2.Neesse A, Krug S, Gress TM, Tuveson DA, Michl P. Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma. Onco Targets Ther. 2013;7:33–43. doi: 10.2147/OTT.S38111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Nahleh Z, Tfayli A, Najm A, El Sayed A, Nahle Z. Heat shock proteins in cancer: targeting the ‘chaperones’. Future Med Chem. 2012;4:927–935. doi: 10.4155/fmc.12.50. [DOI] [PubMed] [Google Scholar]
- 4.Barrera-Chimal J, Perez-Villalva R, Ortega JA, Uribe N, Gamba G, Cortes-Gonzalez C, Bobadilla NA. Intra-renal transfection of heat shock protein 90 alpha or beta (Hsp90alpha or Hsp90beta) protects against ischemia/reperfusion injury. Nephrol Dial Transplant. 2014;29:301–312. doi: 10.1093/ndt/gft415. [DOI] [PubMed] [Google Scholar]
- 5.Milanovic D, Firat E, Grosu AL, Niedermann G. Increased radiosensitivity and radiothermosensitivity of human pancreatic MIA PaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitor NVP-HSP990. Radiat Oncol. 2013;8:42. doi: 10.1186/1748-717X-8-42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gu M, Yu Y, Gunaherath GM, Gunatilaka AA, Li D, Sun D. Structure-activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells. Invest New Drugs. 2014;32:68–74. doi: 10.1007/s10637-013-9987-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Tung CL, Chiu HC, Jian YJ, Jian YT, Chen CY, Syu JJ, Wo TY, Huang YJ, Tseng SC, Lin YW. Down-regulation of MSH2 expression by an Hsp90 inhibitor enhances pemetrexed-induced cytotoxicity in human non-small-cell lung cancer cells. Exp Cell Res. 2014;322:345–54. doi: 10.1016/j.yexcr.2014.02.002. [DOI] [PubMed] [Google Scholar]
- 8.Sato Y, Kojima R, Okumura M, Hagiwara M, Masui S, Maegawa K, Saiki M, Horibe T, Suzuki M, Inaba K. Synergistic cooperation of PDI family members in peroxiredoxin 4-driven oxidative protein folding. Sci Rep. 2013;3:2456. doi: 10.1038/srep02456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Allen S, Goodeve AC, Peake IR, Daly ME. Endoplasmic reticulum retention and prolonged association of a von Willebrand’s disease-causing von Willebrand factor variant with ERp57 and calnexin. Biochem Biophys Res Commun. 2001;280:448–453. doi: 10.1006/bbrc.2000.4139. [DOI] [PubMed] [Google Scholar]
- 10.Chay D, Cho H, Lim BJ, Kang ES, Oh YJ, Choi SM, Kim BW, Kim YT, Kim JH. ER-60 (PDIA3) is highly expressed in a newly established serous ovarian cancer cell line, YDOV-139. Int J Oncol. 2010;37:399–412. doi: 10.3892/ijo_00000688. [DOI] [PubMed] [Google Scholar]
- 11.Menoret A, Drew DA, Miyamoto S, Nakanishi M, Vella AT, Rosenberg DW. Differential proteomics identifies PDIA3 as a novel chemoprevention target in human colon cancer cells. Mol Carcinog. 2014;53(Suppl 1):E11–22. doi: 10.1002/mc.21986. [DOI] [PubMed] [Google Scholar]
- 12.Leys CM, Nomura S, LaFleur BJ, Ferrone S, Kaminishi M, Montgomery E, Goldenring JR. Expression and prognostic significance of prothymosin-alpha and ERp57 in human gastric cancer. Surgery. 2007;141:41–50. doi: 10.1016/j.surg.2006.05.009. [DOI] [PubMed] [Google Scholar]
- 13.He C, Jiang H, Geng S, Sheng H, Shen X, Zhang X, Zhu S, Chen X, Yang C, Gao H. Analysis of whole genomic expression profiles and screening of the key signaling pathways associated with pancreatic cancer. Int J Clin Exp Pathol. 2012;5:537–546. [PMC free article] [PubMed] [Google Scholar]
- 14.Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer. 2009;115:3379–3391. doi: 10.1002/cncr.24396. [DOI] [PubMed] [Google Scholar]
- 15.Xu HT, Yu H, Zhang XY, Shen XY, Zhang KH, Sheng HH, Dai SB, Gao HJ. UNC51-like kinase 1 as a potential prognostic biomarker for hepatocellular carcinoma. Int J Clin Exp Pathol. 2013;6:711–717. [PMC free article] [PubMed] [Google Scholar]
- 16.Zhang X, He C, He C, Chen B, Liu Y, Kong M, Wang C, Lin L, Dong Y, Sheng H. Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Pathol Res Pract. 2013;209:510–515. doi: 10.1016/j.prp.2013.06.005. [DOI] [PubMed] [Google Scholar]
- 17.He CZ, Jiang H, Geng SS, Sheng HH, Shen XY, Zhang XY, Zhu SZ, Chen XM, Yang CQ, Gao HJ. Expression of c-Myc and Fas correlates with perineural invasion of pancreatic cancer. Int J Clin Exp Pathol. 2012;5:339–346. [PMC free article] [PubMed] [Google Scholar]
- 18.Redlak MJ, Miller TA. Targeting PI3K/Akt/HSP90 signaling sensitizes gastric cancer cells to deoxycholate-induced apoptosis. Dig Dis Sci. 2011;56:323–329. doi: 10.1007/s10620-010-1294-2. [DOI] [PubMed] [Google Scholar]
- 19.Laszlo A, Thotala D, Hallahan DE. Membrane phospholipids, EML4-ALK, and Hsp90 as novel targets in lung cancer treatment. Cancer J. 2013;19:238–246. doi: 10.1097/PPO.0b013e31829a68eb. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Centenera MM, Fitzpatrick AK, Tilley WD, Butler LM. Hsp90: still a viable target in prostate cancer. Biochim Biophys Acta. 2013;1835:211–218. doi: 10.1016/j.bbcan.2012.12.005. [DOI] [PubMed] [Google Scholar]
- 21.Miyata Y, Nakamoto H, Neckers L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des. 2013;19:347–365. doi: 10.2174/138161213804143725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Mayer P, Harjung A, Breinig M, Fischer L, Ehemann V, Malz M, Scherubl H, Britsch S, Werner J, Kern MA, Blaker H, Schirmacher P, Bergmann F. Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors. Endocr Relat Cancer. 2012;19:217–232. doi: 10.1530/ERC-11-0227. [DOI] [PubMed] [Google Scholar]
- 23.Modi S, Saura C, Henderson C, Lin NU, Mahtani R, Goddard J, Rodenas E, Hudis C, O’Shaughnessy J, Baselga J. A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer. Breast Cancer Res Treat. 2013;139:107–113. doi: 10.1007/s10549-013-2510-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Iyer G, Morris MJ, Rathkopf D, Slovin SF, Steers M, Larson SM, Schwartz LH, Curley T, DeLaCruz A, Ye Q, Heller G, Egorin MJ, Ivy SP, Rosen N, Scher HI, Solit DB. A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors. Cancer Chemother Pharmacol. 2012;69:1089–1097. doi: 10.1007/s00280-011-1789-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Hubbard J, Erlichman C, Toft DO, Qin R, Stensgard BA, Felten S, Ten Eyck C, Batzel G, Ivy SP, Haluska P. Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors. Invest New Drugs. 2011;29:473–480. doi: 10.1007/s10637-009-9381-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Oh WK, Galsky MD, Stadler WM, Srinivas S, Chu F, Bubley G, Goddard J, Dunbar J, Ross RW. Multicenter phase II trial of the heat shock protein 90 inhibitor, retaspimycin hydrochloride (IPI-504), in patients with castration-resistant prostate cancer. Urology. 2011;78:626–630. doi: 10.1016/j.urology.2011.04.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Liu H, Zhang T, Chen R, McConkey DJ, Ward JF, Curley SA. Multiple kinase pathways involved in the different de novo sensitivity of pancreatic cancer cell lines to 17-AAG. J Surg Res. 2012;176:147–153. doi: 10.1016/j.jss.2011.09.017. [DOI] [PubMed] [Google Scholar]
- 28.Ogata M, Naito Z, Tanaka S, Moriyama Y, Asano G. Overexpression and localization of heat shock proteins mRNA in pancreatic carcinoma. J Nippon Med Sch. 2000;67:177–185. doi: 10.1272/jnms.67.177. [DOI] [PubMed] [Google Scholar]
- 29.Bapat AA, Hostetter G, Von Hoff DD, Han H. Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer. 2011;11:695–707. doi: 10.1038/nrc3131. [DOI] [PubMed] [Google Scholar]
- 30.Gil Z, Cavel O, Kelly K, Brader P, Rein A, Gao SP, Carlson DL, Shah JP, Fong Y, Wong RJ. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst. 2010;102:107–118. doi: 10.1093/jnci/djp456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Erlejman AG, Lagadari M, Toneatto J, Piwien-Pilipuk G, Galigniana MD. Regulatory role of the 90-kDa-heat-shock protein (Hsp90) and associated factors on gene expression. Biochim Biophys Acta. 2014;1839:71–87. doi: 10.1016/j.bbagrm.2013.12.006. [DOI] [PubMed] [Google Scholar]
- 32.Calderwood SK. Molecular cochaperones: tumor growth and cancer treatment. Scientifica (Cairo) 2013;2013:217513. doi: 10.1155/2013/217513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Chen WS, Chen CC, Chen LL, Lee CC, Huang TS. Secreted heat shock protein 90alpha (HSP90alpha) induces nuclear factor-kappaB-mediated TCF12 protein expression to down-regulate E-cadherin and to enhance colorectal cancer cell migration and invasion. J Biol Chem. 2013;288:9001–9010. doi: 10.1074/jbc.M112.437897. [DOI] [PMC free article] [PubMed] [Google Scholar]