Quantification of tumor stroma as a biomarker in pancreatic adenocarcinoma.

Torphy, Robert J.; Volmar, Keith E.; Rashid, Naim; Cader, Sonia; Johansen, Julia S.; Hollingsworth, Michael A.; Collisson, Eric A.; Yeh, Jen Jen

doi:10.1200/jco.2015.33.15_suppl.4021

Cited by 3 publications

(4 citation statements)

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“…Our histopathologic analyses suggest a better prognosis for tumors exhibiting high stroma content. Along this line, a recent study revealed a positive effect of tumor stroma on OS and RFS in a cohort of curatively resected hPDAC (28). Furthermore, in a study on neoadjuvant chemoradiation, patients exhibiting higher stroma content (and higher perfusion values) exhibited better response and outcome despite an inverse correlation of tumor stroma and gemcitabine delivery (29).…”

Section: Discussionmentioning

confidence: 93%

Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer

Heid

Steiger

Trajkovic‐Arsic

et al. 2017

Clinical Cancer Research

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Tumor heterogeneity is a hallmark of pancreatic ductal adenocarcinoma (PDAC). It determines tumor biology including tumor cellularity (i.e., amount of neoplastic cells and arrangement into clusters), which is related to the proliferative capacity and differentiation and the degree of desmoplasia among others. Given the close relation of tumor differentiation with differences in progression and therapy response or, e.g., the recently reported protective role of tumor stroma, we aimed at the noninvasive detection of PDAC groups, relevant for future personalized approaches. We hypothesized that histologic differences in PDAC tissue composition are detectable by the noninvasive diffusion weighted- (DW-) MRI-derived apparent diffusion coefficient (ADC) parameter. PDAC cellularity was quantified histologically and correlated with the ADC parameter and survival in genetically engineered mouse models and human patients. Histologic analysis showed an inverse relationship of tumor cellularity and stroma content. Low tumor cellularity correlated with a significantly prolonged mean survival time (PDAC = 21.93 months vs. PDAC = 12.7 months; log-rank < 0.001; HR = 2.23; CI, 1.41-3.53). Multivariate analysis using the Cox regression method confirmed tumor cellularity as an independent prognostic marker ( = 0.034; HR = 1.73; CI, 1.04-2.89). Tumor cellularity showed a strong negative correlation with the ADC parameter in murine ( = -0.84; CI, -0.90- -0.75) and human ( = -0.79; CI, -0.90 to -0.56) PDAC and high preoperative ADC values correlated with prolonged survival (ADC = 41.7 months; ADC = 14.77 months; log rank, = 0.040) in PDAC patients. This study identifies high tumor cellularity as a negative prognostic factor in PDAC and supports the ADC parameter for the noninvasive identification of PDAC groups. .

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Section: Discussionmentioning

confidence: 93%

Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer

Heid

Steiger

Trajkovic‐Arsic

et al. 2017

Clinical Cancer Research

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“…16 Also, patients with resected tumors with high stromal density had better survival after surgery and those with low stromal density had more aggressive disease. 17 A number of stroma-targeted therapies have yielded promising results in the pre-clinical setting and are currently under evaluation in clinical trials including PEGPH20, 18 which depletes hyaluronan, a component of the stromal ECM, TH-302, 19 a hypoxia-activated chemotherapeutic, modified vitamin D, 20 which targets the vitamin D receptor on PSCs resulting in stromal reprogramming, and losartan, 21 an angiotensin II type 1 receptor inhibitor which inhibits PSC activity. Understanding the biology of the stroma will be as important as understanding tumor biology and should result in better targeted treatments with better therapeutic delivery, leading to improvements in patient survival of pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Prolonged myofibroblast depletion in a transgenic mouse model resulted in more frequent precursor lesions (pancreatic intraepithelial neoplasms [PanINs]), and tumors became more metastatic and highly proliferative . Also, patients with resected tumors with high stromal density had better survival after surgery and those with low stromal density had more aggressive disease . A number of stroma‐targeted therapies have yielded promising results in the pre‐clinical setting and are currently under evaluation in clinical trials including PEGPH20, which depletes hyaluronan, a component of the stromal ECM, TH‐302, a hypoxia‐activated chemotherapeutic, modified vitamin D, which targets the vitamin D receptor on PSCs resulting in stromal reprogramming, and losartan, an angiotensin II type 1 receptor inhibitor which inhibits PSC activity.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of group 1 p21‐activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer

Yeo

Phillips

Baldwin

et al. 2017

Intl Journal of Cancer

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Pancreatic cancer remains one of the most lethal of all solid tumors. Pancreatic stellate cells (PSCs) are primarily responsible for the fibrosis that constitutes the stroma and p21-activated kinase 1 (PAK1) may have a role in signalling pathways involving PSCs. This study aimed to examine the role of PAK1 in PSCs and in the interaction of PSCs with pancreatic cancer cells. Human PSCs were isolated using the modified outgrowth method. The effect of inhibiting PAK1 with group 1 PAK inhibitor, FRAX597, on cell proliferation and apoptosis in vitro was measured by thymidine incorporation and annexin V assays, respectively. The effect of depleting host PAK1 on the survival of mice with pancreatic Pan02 cell tumors was evaluated using PAK1 knockout (KO) mice. PAK1 was expressed in isolated PSCs. FRAX597 reduced the activation of PSCs, inhibited PSC proliferation, and increased PSC apoptosis at least in partial by inhibiting PAK1 activity. The decreased expression and activity of PAK1 in PAK1 KO mice tumors was associated with an increased mouse survival. These results implicate PAK1 as a regulator of PSC activation, proliferation and apoptosis. Targeting stromal PAK1 could increase therapeutic response and survival of patients with pancreatic cancer.

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“…Prolonged myofibroblast depletion in a transgenic mouse model with deleted αSMA myofibroblasts resulted in more frequent precursor lesions (PanINs), and tumours were more commonly metastatic and highly proliferative (171). Also, patients with resected tumours with high stromal density had better survival after surgery compared to those with low stromal density who had more aggressive disease (207). A number of stroma-targeted therapies have yielded promising results in the preclinical setting and are currently under evaluation in clinical trials including PEGPH20 (86), which depletes hyaluronan, a component of the stromal ECM;…”

Section: Introductionmentioning

confidence: 99%

The Role of p21-Activated Kinases in Pancreatic Cancer

Yeo

Baldwin

et al. 2015

Pancreas

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Pancreatic cancer is an aggressive cancer with a poor prognosis and an overall 5-year survival rate of less than 5%. Management has not improved significantly over the last 30 years, and a better understanding of the genetic and molecular changes that occur is urgently required. Many of these changes appear to involve the p21-activated kinases (PAKs). The PAK family consists of 6 isoforms, 2 of which, PAK1 and PAK4, are up-regulated and/or hyperactivated in pancreatic cancer. p21-Activated kinases can mediate many different cellular processes especially those contributing to cancer development and progression. These processes include the regulation of cytoskeletal dynamics and cell adhesion, the evasion of apoptosis, and the promotion of cell survival, proliferation, migration, and invasion. p21-Activated kinases may also be involved in characteristics unique to pancreatic tumors, such as interplay with the pancreatic stroma, the re-emergence of embryonic pathways, and the involvement of a subset of microRNAs and heat shock proteins. This review highlights the potential role of PAKs in pancreatic cancer and provides a foundation for more effective therapeutics to improve our current treatment of pancreatic cancer.

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Quantification of tumor stroma as a biomarker in pancreatic adenocarcinoma.

Cited by 3 publications

References 0 publications

Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer

Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer

Inhibition of group 1 p21‐activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer

The Role of p21-Activated Kinases in Pancreatic Cancer

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