DOI:10.1111/j.1477-2574.2010.00177.

x HPB

ORIGINAL ARTICLE

Prognostic significance of PINCH signalling in human pancreatic

ductal adenocarcinoma
Courtney L. Scaife1, Jill Shea1, Lyska Emerson2, Kenneth Boucher3, Matthew A. Firpo1, Mary C. Beckerle4 and
Sean J. Mulvihill1
1
Department of Surgery, 2Department of Pathology and 3Department of Biostatistics, 4Department of Biology and Oncological Science, University of Utah,
Salt Lake City, UT, USA

Abstract hpb_177 352..358

Objective: Prognostic markers for pancreatic ductal adenocarcinoma (PDA) have failed to accurately
predict patient prognosis. Recently, interest has developed in the accuracy of integrin-associated PINCH
protein expression in human cancers as a predictive marker of tumour status. The goal of this study was
to define the expression of PINCH protein in PDA.
Methods: Human PDA samples and orthotopic tumours from a murine model were analysed by immu-
nohistochemistry for PINCH expression. In the animal model, PINCH expression was compared between
primary and metastatic tumours. In the human samples, PINCH expression was correlated with stage,
nodal involvement, margin status and overall survival.
Results: In the murine model, there was greater PINCH expression in metastatic tumours than in primary
tumours. In the human PDA samples, greater staining for PINCH in the tumour cells was correlated with
higher T status. Additionally, high PINCH expression in the stroma was associated with decreased overall
survival.
Conclusions: Findings of increased PINCH protein in more advanced stages of human PDA, as well as
in metastatic tumours in the animal model, support the hypothesis that PINCH is an important controller
of cell survival and migration. Additionally, the importance of the differential expression of PINCH in the
human tumour and stroma warrants further evaluation.

Received 31 August 2009; accepted 3 March 2010

Correspondence
Courtney L. Scaife, Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT
84132, USA. Tel: + 1 801 518 7738. Fax: + 1 801 581 6612. E-mail: [email protected]

Introduction pathologic positive margin rate at resection remains 50–75%.

These outcomes imply a particularly invasive tumour phenotype.
Pancreatic ductal adenocarcinoma (PDA) remains one of the
Recent studies have suggested an important role for the inter-
most poorly controlled solid organ malignancies in the USA and
action of tumour cells and tumour-associated stroma cells in
is the fourth leading cause of cancer-related deaths.1 Surgical
the regulation of cell–cell adhesion and invasion.2,3 The adhesion
resection remains the primary treatment. Yet, nearly 80% of
of cells to the extracellular matrix (ECM) is essential for cell
surgically resected patients with localized pancreatic cancer die
migration, division and cell–cell signalling.4,5 Variations in this
as a result of recurrent or metastatic disease.1 Additionally, the
interaction between the tumour and surrounding tissues may
facilitate the survival, malignant transformation and invasion of
tumour cells.3,6–9 Integrin-associated proteins facilitate this ab-
This paper is based on presentations given at the International Hepato- normal signalling and control.4,5,9 PINCH, a particularly interest-
Pancreato-Biliary Association Meeting, Feb 27–March 2 2008, Mumbai ing new cysteine-histidine-rich integrin-associated protein, is an
(Scaife CL, Firpo MA, Emerson L, Shea JE, Boucher K, Beckerle MC, Mul- important component of the focal adhesion complexes that link
vihill SJ; Prognostic significance of PINCH signalling in human pancreatic the ECM to the support structures within the cell and is expressed
adenocarcinoma) and the Pancreas Club, May 30–31 2009, Chicago, IL, USA in many human tissues. PINCH expression has been shown to be
(Shea JE, Emerson LL, Mulvihill SJ, Scaife CL; Metastatic PDA tumours upregulated in many malignant tissues, including breast, colon,
express greater levels of PINCH than primary tumours). prostate, lung and oral squamous cell carcinomas.10–12 In these

HPB 2010, 12, 352–358 © 2010 International Hepato-Pancreato-Biliary Association

HPB 353

tumours PINCH expression localizes to the peri-tumoral stroma Each patient had been diagnosed with pancreatic head adeno-
cells, particularly at the tumour’s invasive edges. Additionally, carcinoma and had undergone an en bloc resection with a
PINCH expression is correlated with poorer patient prognosis in pancreaticoduodenectomy. The study pathologist analysed the
colon and oral epithelial cancers.10,12 The aggressive nature and tissue blocks to determine which blocks represented the primary
strong desmoplastic response in PDA implies that PINCH expres- tumours and tumour margins. New tissue slides for immuno-
sion may be an important outcome marker for PDA and may histochemistry were made from these identified sections. With
identify which patients are more likely to experience recurrence. the approval of the institutional review board, each patient’s chart
The purpose of this study was to investigate the expression of was reviewed for tumour staging, nodal status and margin status
PINCH in PDA and to determine the association between PINCH at surgical resection, recurrence, and overall and disease-free
expression and tumour aggressiveness or patient prognosis. survival.
We initially compared PINCH expression between primary and
metastatic tumours in an orthotopic PDA animal model. We Immunohistochemistry
subsequently correlated PINCH expression in primary human Immunohistochemical staining was performed on 4-mm thick
paraffin-embedded PDA tumours, within both the tumour and sections of formalin-fixed, paraffin-embedded tissue. Prior to
the peri-tumoral stroma cells, with disease stage and patient out- staining, heat-induced epitope retrieval (HIER) was performed in
comes. We hypothesized that PINCH protein expression would be citrate buffer, pH 6.0, in an electric pressure cooker (DC2000;
greater in the peri-tumoral stroma compared with tumour cells BioCare Medical LLC, Walnut Creek, CA, USA). Samples were
and that the degree of PINCH protein expression would correlate then stained for PINCH (BD Biosciences, Inc., San Jose, CA,
with a more invasive tumour or poorer patient prognosis. USA). Following incubation with the primary antibody, samples
were processed using a commercially available Alkaline Phos-
Materials and methods phatase Kit (Vector Laboratories, Inc., Burlingame, CA, USA). A
Cell culture pathologist (author LE) analysed the samples to determine the
The human pancreatic cancer cell line AsPc1 was obtained from percentage of cells positively stained for PINCH, as well as the
the American Type Culture Collection (Rockville, MD, USA). intensity of the staining. The pathologist was blinded to tumour
Cells were maintained in DMEM supplemented with 10% heat- location for the primary and metastatic tumours from the animal
inactivated foetal bovine serum (Gibco, Inc., Grand Island, NY, PDA model. The index for the proportion of cells stained for
USA). Cells were cultured at 37 °C in a 5% CO2 incubator. The cell PINCH was defined by positive staining for PINCH of: (1) 0–25%;
line was transfected with and stably expressed red fluorescent (2) 26–50%; (3) 51–75%, and (4) 76–100%. Intensity of staining
protein (RFP), as previously described.13 for PINCH was scored as: (0) no staining; (1) mild staining; (2)
moderate staining, and (3) strong staining.
Orthotopic tumour production
Male nude mice (NCR-nu/nu) aged 4–6 weeks were utilized for Statistics
the orthotopic tumour model. All studies were conducted with the In the analysis of animal tumours, a t-test was utilized to deter-
approval and guidance of the University of Utah Institutional mine if there were differences in the proportion and intensity
Animal Care and Use Committee. indices for staining for PINCH in the primary orthotopic
For the tumour induction surgery, mice were anesthetized with tumour and peri-tumoral stroma compared with metastatic
isoflurane and the tail of the pancreas was exposed through a left tumours. A t-test was also utilized to determine if there were any
subcostal 4-mm incision into the peritoneal cavity.13 Mice received differences in the proportion and intensity indices for staining
a single sub-capsular injection of 1.5 ¥ 106 RFP-labelled AsPc1 for PINCH between the tumour and stroma cells within the
cells suspended in 150 mL of serum-free media (DMEM). The tumour.
abdomen was closed using two interrupted 6–0 silk sutures In the analysis of human tumours, a t-test was utilized to deter-
closing skin and muscle simultaneously. All procedures were mine if there were differences in the proportion and intensity
carried out utilizing a 12¥ Universal S3B microscope (Carl Zeiss, indices for staining for PINCH in the tumour cells compared with
Inc., Thornwood, NY, USA). Tumours were allowed to progress the peri-tumoral stroma cells. A non-parametric Spearman’s rank
for 8 weeks. At 8 weeks the animals were killed, the tumours correlation was performed to determine whether staining corre-
removed, sites of metastases noted, and metastatic tumours lated with T and N tumour status. The final goal was to determine
removed. Primary and metastatic tumours were fixed in 10% if staining for PINCH in the tumour and peri-tumoral stroma
formalin, dehydrated, and embedded in paraffin. correlated with overall survival. The data were divided into groups
near the median and a likelihood ratio test using the Cox propor-
Patients tional hazards model was performed. The estimated hazard ratio
Utilizing our institution’s clinical cancer research database (Cox model) and the median survival in each group (estimated
and tissue bank, we randomly identified 20 PDA patients’ from the Kaplan–Meier curve) were also determined. Statistical
paraffin-embedded block specimens and two normal controls. significance was set at P < 0.05.

HPB 2010, 12, 352–358 © 2010 International Hepato-Pancreato-Biliary Association

354 HPB

Results compared with the metastatic peri-tumoral stoma cells. There

PINCH expression in animal orthotopic PDA tumours were no differences in staining for PINCH between the various
Nine of the 10 animals developed a primary orthotopic tumour. metastatic sites, but the small sample size at each location limits
All of these nine animals developed distant metastases (n = 19 the significance of this finding.
metastases). The location of the metastases included the dia-
phragm (n = 6/19), mesentery (n = 5/19), liver (n = 4/19) and
peritoneal cavity (n = 4/19). There was constituent PINCH PINCH expression in human PDA tumours
expression in the mouse pancreas islet cells and acinar cells PINCH protein was constitutively expressed in the control pan-
(Fig. 1). The orthotopic tumour did not show significantly more creas, with greater staining in the islet cells than in the pancreatic
staining than the normal surrounding pancreas. The mouse acinar cells (Fig. 3). Staining for PINCH was greater according to
model tumours showed equivalent staining when the peri- both the proportion of stained cells and staining intensity in the
tumoral stroma cells were compared with the tumour cells PDA peri-tumoral stroma cells compared with the tumour cells
(Fig. 2). (Fig. 4). All the patient samples demonstrated PINCH expression
Staining for PINCH, both by proportion and intensity of stain- in tumour and peri-tumoral stroma cells. In 70% (14/20) of cases,
ing, was higher in the metastatic tumour cells compared with the >50% of the peri-tumoral stroma cells stained positive for
primary orthotopic tumour cells (Figs 1 and 2). By contrast with PINCH. By contrast, only 15% (3/20) of the tumour samples
the tumour cells, there were no differences in staining for PINCH showed positive staining for PINCH on >50% of the tumour cells.
within the peri-tumoral stoma cells of the primary tumours The differences in staining between the tumour and peri-tumoral

(A) (B)

Figure 1 Light microscope images. (A) Mouse primary tumour immunohistochemically stained for PINCH, demonstrating strong constitutive
expression in the pancreas acinar cells (P). Both the tumour and peri-tumoral stroma cells of the primary tumour stain positive for PINCH.
(B) Mouse metastatic tumour cells stain to a greater degree than primary tumour cells. (Original magnification 200¥ in both images)
positive staining for PINCH

4
Index for proportion of

*
Index for intensity of
staining for PINCH

4
*
3
3
2
2

1 1

0 0
Tumour cells Tumour stroma cells Tumour cells Tumour stroma cells
(A) Metastatic tumour Primary tumour (B) Metastatic tumour Primary tumour
Figure 2 Comparisons between tumour cells and tumour stroma cells in metastatic and primary tumours for (A) the proportion of cells
positively stained for PINCH and (B) staining intensity. The proportion of cells stained for PINCH and staining intensity were statistically
greater in tumour stroma compared with tumour cells. *P < 0.05; data are reported as mean ⫾ standard error

HPB 2010, 12, 352–358 © 2010 International Hepato-Pancreato-Biliary Association

HPB 355

(A) (B)

Figure 3 Light microscope images. (A) Human control pancreas in which the islet cells (I) of the pancreas stain with a higher intensity
compared with the acinar cells (A). (B) Human pancreatic ductal adenocarcinoma tissue demonstrating staining for PINCH was stronger in
the peri-tumoral stroma cells (S) compared with the tumour cells (T). (Original magnification 400¥ in both images)
positive staining for PINCH

4 2.0
Index for proportion of

Index for intensity of

*
staining for PINCH

1.8
* 1.6
3
1.4
1.2
2 1.0
0.8
0.6
1
0.4
0.2
0 0.0
(A) Tumour stroma cells Tumour cells (B) Tumour stroma cells Tumour cells
Figure 4 Comparisons between tumour stroma cells and tumour cells for (A) the proportion of cells positively stained for PINCH and (B)
staining intensity. The proportion of cells stained for PINCH and staining intensity were statistically greater in tumour stroma compared with
tumour cells. *P < 0.05; data are reported as mean ⫾ standard error

stroma cells were also qualitatively evident by light microscopy stroma was not statistically correlated with either T or N status.
(Fig. 3). Staining for PINCH and margin status were not statistically
correlated (P > 0.6; data not presented).
PINCH expression correlated with disease stage The data were also analysed to determine if there were any
and patient outcomes correlations between survival and staining for PINCH. There was
Patients a trend toward significance between the proportion of cells posi-
Demographic data for the 20 patients are presented in Table 1, tively stained for PINCH (P = 0.07) and staining intensity (P =
including gender, age, T stage, N stage, margin status and survival. 0.06) in the peri-tumoral stroma cells and survival, with stronger
Patients included 12 women with an average age of 68 ⫾ 14 years staining associated with poorer survival. The median survival was
and eight men with an average age of 62 ⫾ 13 years. There were 884 days in subjects with low PINCH expression (n = 7) compared
no correlations between patient gender or age and staining for with 337 days in subjects with high PINCH expression (n = 13),
PINCH. The majority of our patients had T3 tumours (n = 13). with a hazard ratio of 2.3 (Fig. 5).
According to American Joint Committee on Cancer (AJCC)
staging, one patient had stage I cancer, 10 had stage II cancer, and
Discussion
nine had stage III cancer. Increased staining for PINCH in the
tumour cells, by both proportion and intensity of staining, The data from the present investigation support the hypothesis
was correlated with higher T status (P < 0.05) (Table 2). PINCH that PINCH plays an important role in the progression of cancer.
expression in the tumour cells was not statistically correlated with Specifically, in the orthotopic animal model of PDA, we observed
N status. Additionally, staining for PINCH in the peri-tumoral greater PINCH expression in the invasive metastatic tumours

HPB 2010, 12, 352–358 © 2010 International Hepato-Pancreato-Biliary Association

356 HPB

Table 1 Patient demographic information

Patient Gender Age at T status N status Positive Positive retro- Survival,
diagnosis, pancreatic peritoneal days
years margin margin
1 F 77 2 1 No No 995
2 M 52 3 1 No No 267
3 M 65 1 0 No No 545
4 F 60 3 0 No No 1086
5 F 67 4 1 No Yes 157
6 F 35 3 1 No No 221
7 F 73 3 0 No No 457
8 M 77 3 1 No Yes 207
9 F 71 1 1 No Yes 921
10 M 37 3 1 No Yes 337
11 F 82 3 0 No No 2250
12 M 71 3 1 No No 399
13 F 73 3 0 No No 424
14 M 56 4 0 No No 884
15 F 80 3 0 No Yes 284
16 M 72 4 1 Yes Yes 222
17 F 73 3 1 No No 1700
18 M 66 1 Yes No 1923
19 F 82 3 1 Yes Yes 310
20 F 48 3 0 Yes No 314

F, female; M, male

Table 2 Spearman's rank correlation coefficients (rs) for PINCH 1.0

expression vs. tumour status (T) and nodal status (N)
Staining for PINCH T status N status 0.8 P = 0.068
a
Tumour cells, proportion 0.493 0.180
Survival

0.6
Tumour cells, intensity 0.477a 0.148
Tumour stroma, proportion -0.022 0.372
0.4
Tumour stroma, intensity 0.179 0.241
a
Statistically positive correlation between PINCH expression and T status 0.2
(P < 0.05)
0.0
0 10 20 30 40 50 60 70
Months
compared with the primary tumours. Secondly, within the human Sample sizes
samples analysed, higher T status and poorer survival correlated PINCH stroma 13 9 3 3
>3.1:
with greater PINCH expression. Thus, in both the animal model PINCH stroma 7 7 4 3 3 3 2
and patient population, PINCH expression correlated with a more <3.0:
invasive and aggressive tumour phenotype. Figure 5 Kaplan–Meier curve demonstrating the correlation between
Another interesting observation concerns the constituent PINCH expression in the stroma and survival. Individuals with lower
PINCH expression within the normal pancreas seen in both the PINCH expression on average lived longer (P = 0.068). No patients
mouse PDA model and the human control samples. Although this were lost to follow-up and thus no censor points are indicated on the
was not quantitatively determined, there did not appear to be graph. The median survival was 884 days in subjects with low
greater PINCH expression within the tumours compared with PINCH (n = 7) compared with 337 days in subjects with high PINCH
(n = 13), with a hazard ratio of 2.3
the normal pancreas. This is by contrast with other cancers.
Wang-Rodriguez et al. confirmed increased expression of PINCH
protein in breast, prostate, lung and colorectal cancers relative to
healthy tissue.11 More recently, it has been shown that PINCH

HPB 2010, 12, 352–358 © 2010 International Hepato-Pancreato-Biliary Association

HPB 357

expression is greater in oesophageal and oral squamous cell size.14 Similar findings have been observed in oral epithelial
carcinoma, colorectal cancer and gliomas relative to normal tumours, with greater PINCH expression in nodal metastases
tissue.12,14–16 Taken together, the observation by others of greater relative to primary tumours, and in colorectal cancer, with
PINCH expression in the tumour, as well as our demonstration of greater PINCH expression correlating to poorer patient progno-
a correlation between PINCH expression and poorer patient sis.10,15 We confirmed a similar pattern whereby increased inva-
prognosis, suggest that PINCH expression may be an important siveness or tumour aggressiveness was correlated with increased
component of cancer progression in general. PINCH expression in PDA. Several findings corroborate this
Another important finding of the present investigation is that conclusion: firstly, in the murine orthotopic model, PINCH
PINCH expression appears to be stronger in the stroma cells expression was significantly higher in metastatic tumour tissue
adjacent to the cancer cells in human PDA. PINCH expression in than in primary tumours; secondly, in the human PDA tissues,
the peri-tumoral stroma cells is roughly double that of the cancer tumour T status correlated with increased PINCH expression,
cells, in terms of both the proportion of cells stained and the and, finally, a trend toward increased PINCH expression in PDA
intensity of staining. PINCH expression is also demonstrated to a tumours with poorer patient survival is probably important. We
greater degree in the peri-tumoral stroma tissue of other cancers feel that the trend in survival failed to reach statistical signifi-
compared with the adjacent cancer cells.11,12,14–16 Evidence demon- cance based on the small number of patients and the generally
strating that the interactions between peri-tumoral stroma cells poor prognosis of all patients with PDA. However, the human
and cancer cells may play an important part in the progression data on T status and survival combined with the animal data on
and metastases of cancer is beginning to accumulate.2,3,6–8 This metastatic tumours suggest that PINCH plays an important role
may be even more important in PDA, as it is associated not only in the progression of PDA.
with earlier incidences of metastases, but also with a much greater
desmoplastic response. Pancreatic stoma cells have been shown to Conclusions
activate the ERK and AKT pathways and thus are strong promot-
ers of growth and invasion.2,3,8 These same pathways are also acti- PINCH protein may function as a regulator or signal for ECM
vated by PINCH.4,5,17 Thus PINCH in the peri-tumoral stroma invasion and cellular migration. Findings of increased PINCH
cells may be an important regulator of the growth and migration protein in more advanced stages of human PDA, as well as in
of these cells, as well as adjacent cancer cells, and therefore a good metastatic tumours from the animal model, support this hypo-
marker for determining the invasiveness of a tumour. thesis. Additionally, the importance of the differential expression
One interesting finding was that this differential expression of PINCH in the human tumour and stroma warrants further
of PINCH between stroma and cancer cells did not exist in the evaluation.
animal model. One possible explanation for this might be that the
cancer cells in the animal model were of human origin, whereas Conflicts of interest
None declared.
the stromal cells were of mouse origin. Thus, expression differ-
ences may depend on species origin. Despite these differences,
PINCH expression still appeared to correlate with tumour pro- References
1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. (2007) Cancer
gression in both the human samples and the animal model.
statistics, 2007. CA Cancer J Clin 57:43–66.
There are other pathways by which PINCH could influence
2. Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A
the transformation and progression of PDA. Specifically, PINCH
et al. (2008) Cancer-associated stromal fibroblasts promote pancreatic
has a binding site for Nck-2 and integrin-linked kinase (ILK).4,5 tumor progression. Cancer Res 68:918–926.
Nck-2 is involved in growth factor mediating signalling, as well as 3. Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z, Parker NR et al. (2008)
actin cytoskeleton remodelling.18 The interaction of PINCH and Pancreatic stellate cells: partners in crime with pancreatic cancer cells.
Nck-2 directly links PINCH to the actin polymerization process Cancer Res 68:2085–2093.
and therefore it is likely that PINCH plays a role in cytoskeleton 4. Fukuda T, Chen K, Shi X, Wu C. (2003) PINCH-1 is an obligate partner of
motility at cell–ECM adhesions. The binding of PINCH is also a integrin-linked kinase (ILK) functioning in cell shape modulation, motility,
key regulator of ILK expression and is important for the local- and survival. J Biol Chem 278:51324–51333.
ization of ILK to the cell membrane.4,5 Disruption of the binding 5. Xu Z, Fukuda T, Li Y, Zha X, Qin J, Wu C. (2005) Molecular dissection of
PINCH-1 reveals a mechanism of coupling and uncoupling of cell shape
of these two proteins results in alterations to cell motility, as
modulation and survival. J Biol Chem 280:27631–27637.
well as survival. In recognition of the role of PINCH protein
6. Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK et al.
signalling in malignant transformation, many investigators
(2004) Desmoplastic reaction in pancreatic cancer: role of pancreatic
have hypothesized that PINCH protein expression would be stellate cells. Pancreas 29:179–187.
increased in more aggressive tumours. This has been docu- 7. Schneider E, Schmid-Kotsas A, Zhao J, Weidenbach H, Schmid RM,
mented in colorectal cancers, gliomas and oral epithelial Menke A et al. (2001) Identification of mediators stimulating proliferation
cancers.12,14–16 Specifically, PINCH expression is greater in higher- and matrix synthesis of rat pancreatic stellate cells. Am J Physiol Cell
grade gliomas independent of patient age, gender and tumour Physiol 281:C532–543.

HPB 2010, 12, 352–358 © 2010 International Hepato-Pancreato-Biliary Association

358 HPB

8. McCarroll JA, Phillips PA, Kumar RK, Park S, Pirola RC, Wilson JS et al. an orthotopic mouse model of pancreatic adenocarcinoma. J Gas-
(2004) Pancreatic stellate cell migration: role of the phosphatidylinositol trointest Surg 12:1074–1080.
3-kinase(PI3-kinase) pathway. Biochem Pharmacol 67:1215–1225. 14. Wang MW, Gu P, Zhang ZY, Zhu ZL, Li YM, Zhao HX et al. (2007)
9. Wu C. (2005) PINCH, N(i)ck and the ILK: network wiring at cell-matrix Expression of PINCH protein in gliomas and its clinicopathological sig-
adhesions. Trends Cell Biol 15:460–466. nificance. Oncology 72:343–346
10. Gao J, Arbman G, Rearden A, Sun XF. (2004) Stromal staining for PINCH 15. Zhang JT, Li QX, Wang D, Zhu ZL, Yang YH, Cui DS et al. (2005)
is an independent prognostic indicator in colorectal cancer. Neoplasia Up-regulation of PINCH in the stroma of oral squamous cell carcinoma
6:796–801. predicts nodal metastasis. Oncol Rep 14:1519–1522.
11. Wang-Rodriguez J, Dreilinger AD, Alsharabi GM, Rearden A. (2002) 16. Zhao ZR, Zhang ZY, Cui DS, Jiang L, Zhang HJ, Wang MW et al. (2006)
The signaling adapter protein PINCH is up-regulated in the stroma Particularly interesting new cysteine-histidine rich protein expression in
of common cancers, notably at invasive edges. Cancer 95:1387– colorectal adenocarcinomas. World J Gastroenterol 12:298–301.
1395. 17. Chen K, Tu Y, Zhang Y, Blair HC, Zhang L, Wu C. (2008) PINCH-1
12. Zhu Z, Yang Y, Zhang Y, Wang Z, Cui D, Zhang J et al. (2008) PINCH regulates the ERK-Bim pathway and contributes to apoptosis resistance
expression and its significance in esophageal squamous cell carcinoma. in cancer cells. J Biol Chem 283:2508–2517.
Dis Markers 25:75–80. 18. Vaynberg J, Fukuda T, Chen K, Vinogradova O, Velyvis A, Tu Y et al.
13. Scaife CL, Shea JE, Dai Q, Firpo MA, Prestwich GD, Mulvihill SJ. (2008) (2005) Structure of an ultraweak protein-protein complex and its crucial
Synthetic extracellular matrix enhances tumor growth and metastasis in role in regulation of cell morphology and motility. Mol Cell 17:513–523.

HPB 2010, 12, 352–358 © 2010 International Hepato-Pancreato-Biliary Association