Is metastatic pancreatic cancer an untargetable malignancy?

Kourié, Hampig Raphaël; Gharios, Joseph; Elkarak, Fadi; Antoun, Joëlle; Ghosn, Marwan

doi:10.4251/wjgo.v8.i3.297

Cited by 8 publications

(7 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer accounting for >90% of the diagnosed cases (1). Currently, treatment options for PDAC are scarce (1) and new therapeutic targets are subject to intensive research (2,3). Matrix metalloproteinases (MMPs) are zinc-dependent proteases that contribute to development and tissue homeostasis, and modulate cancer progression by digesting a variety of substrates (4).…”

Section: Introductionmentioning

confidence: 99%

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

Grünwald

Vandooren

Gerg

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

Matrix metalloproteinase 9 (MMP-9/Gelatinase B) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and plays a central role in tumor cell invasion and metastasis. Here we complemented mechanistic insights in the cancer biology of MMP-9 and investigated the effects of specific long-term lossof-function, by genetic ablation, of MMP-9 on PDAC initiation and progression in the well-established KPC mouse model of spontaneous PDAC. Tumor growth and progression were analyzed by histopathology and IHC. Invasive growth of PDAC cells was analyzed by both in vitro (proliferation, survival, migration, invasion assays) and in vivo (experimental metastasis assays) methods. Retroviral shRNAi was used to knockdown target genes (MMP-9, IL6R). Gene expression was analyzed by qRT-PCR, immunoblot, ELISA, in situ hybridization, and zymography. PDAC tumors from MMP-9-deficient mice were dramatically larger, more invasive, and contained more stroma.Yet, ablation of MMP-9 in PDAC cells did not directly promote invasive growth. Interestingly, systemic ablation of MMP-9 led to increased IL6 levels resulting from abrogation of MMP-9-dependent SCF signaling in the bone marrow. IL6 levels in MMP-9 À/À mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL6 receptor (IL6R). Interference with IL6R blocked the increased invasion and metastasis of PDAC cells in MMP-9-deficient hosts. In conclusion, ablation of systemic MMP-9 initiated fatal communication between maintenance of physiological functions of MMP-9 in the bone marrow and invasive growth of PDAC via the IL6/ IL6R/STAT3 axis.Implications: Thus, the beneficial effects of host MMP-9 on PDAC are an important caveat for the use of systemic MMP-9 inhibitors in cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

Grünwald

Vandooren

Gerg

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…1 The inherent difficulty in treating pancreatic cancer is related to late diagnosis and the resistance of pancreatic cancer cells to chemotherapy. 3 These dismal prognoses underscore an important need for more effective therapeutics and for identifying novel therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells

Nguyen

Irby

2016

Cancer Biology & Therapy

View full text Add to dashboard Cite

The prostate apoptosis response protein 4 (Par-4) is a tumor-suppressor that has been shown to induce cancer-cell selective apoptosis in a variety of cancers. The regulation of Par-4 expression and activity is a relatively understudied area, and identifying novel regulators of Par-4 may serve as novel therapeutic targets. To identify novel regulators of Par-4, a co-immunoprecipitation was performed in colon cancer cells, and co-precipitated proteins were identified by mass-spectometry. TRIM21 was identified as a novel interacting partner of Par-4, and further shown to interact with Par-4 endogenously and through its PRY-SPRY domain. Additional studies show that TRIM21 downregulates Par-4 levels in response to cisplatin, and that TRIM21 can increase the resistance of colon cancer cells to cisplatin. Furthermore, forced Par-4 expression can sensitize pancreatic cancer cells to cisplatin. Finally, we demonstrate that TRIM21 expression predicts survival in pancreatic cancer patients. Our work highlights a novel mechanism of Par-4 regulation, and identifies a novel prognostic marker and potential therapeutic target for pancreatic cancer.

show abstract

“…Recent biomolecular progress has led to a better comprehension of pancreatic carcinogenesis; however, the revolutionary targeted and immune therapies have not shown any significant results[2]. Subsequently, cytotoxic drugs remain the backbone of treatment for metastatic pancreatic cancer (mPC).…”

Section: Introductionmentioning

confidence: 99%

Dilemma of first line regimens in metastatic pancreatic adenocarcinoma

Ghosn¹,

Ibrahim²,

Assi³

et al. 2016

WJG

Self Cite

View full text Add to dashboard Cite

Pancreatic cancer is one of the deadliest cancers, ranking fourth among cancer-related deaths. Despite all the major molecular advances and treatment breakthroughs, mainly targeted therapies, the cornerstone treatment of metastatic pancreatic cancer (mPC) remains cytotoxic chemotherapy. In 2016, more than 40 years after the introduction of gemcitabine in the management of mPC, the best choice for first-line treatment has not yet been fully elucidated. Two main strategies have been adopted to enhance treatment efficacy. The first strategy is based on combining non-cross resistant drugs, while the second option includes the development of newer generations of chemotherapy. More recently, two new regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel (GNP), have both been shown to improve overall survival in comparison with gemcitabine alone, at the cost of increased toxicity. Therefore, the best choice for first line therapy is a matter of debate. For some authors, FOLFIRINOX should be the first choice in patients with an Eastern Cooperative Oncology Group score (0-1) given its lower hazard ratio. However, others do not share this opinion. In this paper, we review the main comparison points between FOLFIRINOX and GNP. We analyze the two pivotal trials to determine the similarities and differences in study design. In addition, we compare the toxicity profile of the two regimens as well as the impact on quality of life. Finally, we present studies revealing real life experiences and review the advantages and disadvantages of possible second-line therapies including their cost effectiveness.

show abstract

Is metastatic pancreatic cancer an untargetable malignancy?

Cited by 8 publications

References 58 publications

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells

Dilemma of first line regimens in metastatic pancreatic adenocarcinoma

Contact Info

Product

Resources

About