scholarly journals Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1347 ◽  
Author(s):  
Jeffrey Norton ◽  
Deshka Foster ◽  
Malini Chinta ◽  
Ashley Titan ◽  
Michael Longaker
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Parenchymal Cell ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
The United States ◽  
Cancer Associated Fibroblasts ◽  
Cancer Cell Growth

Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.

scholarly journals The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

2021 ◽  
pp. 1-8
Author(s):  
Mahmood Tavakkoli ◽  
Saeed Aali ◽  
Borzoo Khaledifar ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Angiotensin Receptor Blockers ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
Transforming Growth Factor Β

<b><i>Background:</i></b> Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. <b><i>Summary:</i></b> Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. <b><i>Key Message:</i></b> The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

scholarly journals LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 260 ◽  
Author(s):  
Qing Zhang ◽  
Xiaonan Hou ◽  
Bradley Evans ◽  
Jamison VanBlaricom ◽  
Saravut Weroha ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Ascites Formation ◽  
Tgf Β1

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

scholarly journals Transforming of the Tumor Microenvironment: Implications for TGF-βInhibition in the Context of Immune-Checkpoint Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Stefanie Löffek
Keyword(s):  
Tumor Microenvironment ◽  
Transforming Growth Factor Beta ◽  
Immune Checkpoint ◽  
Transforming Growth Factor ◽  
Treatment Strategies ◽  
Therapy Response ◽  
Initial Therapy ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Oncogenic Signaling

Significant breakthroughs have been achieved in the fields of oncogenic signaling inhibition and particularly immune-checkpoint blockade has triggered substantial enthusiasm during the last decade. Antibody-mediated blockade of negative immune-checkpoint molecules (e.g., PD-1/PD-L1, CTLA-4) has been shown to achieve profound responses in several of solid cancers. Unfortunately, these responses only occur in a subset of patients or, after initial therapy response, these tumors eventually relapse. Thus, elucidating the determinants of intrinsic or therapy-induced resistance is the key to improve outcomes and developing new treatment strategies. Several cytokines and growth factors are involved in the tight regulation of either antitumor immunity or immunosuppressive tumor-promoting inflammation within the tumor microenvironment (TME), of which transforming growth factor beta (TGF-β) is of particular importance. This review will therefore summarize the recent progress that has been made in the understanding of how TGF-βblockade may have the capacity to enhance efficacy of immune-checkpoint therapy which presents a rational strategy to sustain the antitumor inflammatory response to improve response rates in tumor patients. Finally, I will conclude with a comprehensive summary of clinical trials in which TGF-βblockade revealed therapeutic benefit for patients by counteracting tumor relapses.

Correlation of circulating IL-8 levels with improved overall survival in advanced pancreatic cancer patients in response to antisense OT-101 (trabedersen) therapy.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 444-444 ◽  
Author(s):  
Vuong N. Trieu ◽  
Osmond D'Cruz ◽  
Sanjive Qazi ◽  
Kevin Ng ◽  
Larn Hwang
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Transforming Growth Factor Beta ◽  
Plasma Levels ◽  
Transforming Growth Factor ◽  
Advanced Pancreatic Cancer ◽  
Antisense Oligodeoxynucleotide ◽  
Pairwise Correlation ◽  
Time Points ◽  
Ancova Model

444 Background: Overexpression of the transforming growth factor-beta 2 (TGF-β2) has been suggested as a pivotal factor for malignant progression of pancreatic cancer (PAC). OT-101 (Trabedersen) is a phosphorothioate antisense oligodeoxynucleotide target the human TGF-β2 mRNA. A Phase I/II study of OT-101 was characterized by outstanding overall survival (OS) in patients with advanced PAC. In this study, we examined the association between plasma levels of 31 cyto-/chemokines and OS outcomes in PAC patients treated with OT-101. Methods: Plasma levels of 31 cyto-/chemokine were tracked over a period of 11 days at 8 time points during 3 cycles of intravenous OT-101 therapy (140 mg/m2/day) for 12 PAC patients. A mixed ANCOVA model was developed to time evolution of 19 cyto-/chemokine levels with median expression 1 following OT-101 therapy. Pearson pairwise correlation coefficients of cyto-/chemokine levels across all time points and all patients were utilized to construct a correlation cluster to identify co-regulated cyto-/chemokines. Regression and hierarchical cluster analyses were performed to identify potential cytokine signatures. Protein-protein interaction networks were constructed using STRING10 algorithm. Plasma cyto-/chemokine levels were compared with OS outcome. Results: Three highly correlated subsets of cyto-/chemokines (Cluster 1: EGF, MIP-1α, MIP-1b; Cluster 2: FGF-2, IL-1R, MIG, IP-10, IL-15, IFN-α, IL-12A; Cluster 3: IL-2R, IL-6, IL-8, HGF) were identified following OT-101 therapy. An increasing trend was observed among 13 cytokines. 4 of the 12 patients exhibited a consistent increase in MIP-1α and IL-1b. Suppression of TGF-b signaling by OT-101 led to upregulation of IL-15, IP-10 and HGF. 3 significant associations of cyto-/chemokine and OS were observed at Cycle 1 measurements. The ANCOVA model that examined the levels of 31 cyto-/chemokines with OS as the co-variate resulted in IL-8 exhibiting a significant positive association with OS ( P= 0.0039). Conclusions: Levels of IL-8 were positively associated with OS across 12 PAC patients serving as potential biomarkers for treatment outcome following OT-101 therapy. Clinical trial information: NCT00844064.

The role of soluble TGF-beta and its dynamics for predicting the prognosis in unresectable pancreatic cancer patients treated with chemotherapy.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 288-288 ◽  
Author(s):  
Hyunkyung Park ◽  
Ju-Hee Bang ◽  
Ah-Rong Nam ◽  
Ji Eun Park ◽  
Mei Hua Kim ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Disease Progression ◽  
Cancer Patients ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Prognostic Indicator ◽  
Enzyme Linked Immunosorbent Assay ◽  
Unresectable Pancreatic Cancer

288 Background: Transforming growth factor-beta (TGF-β) is a multifunctional regulatory factor. Here, we measured serum soluble TGF-β (sTGF-β) levels and evaluated its dynamics and prognostic capabilities during chemotherapy in unresectable pancreatic cancer patients. Methods: Sixty patients treated with FOLFIRINOX as the first-line palliative chemotherapy were prospectively enrolled. We prospectively collected blood samples at the time of diagnosis, first response assessment, and disease progression and measured serum sTGF-β using an enzyme-linked immunosorbent assay. Results: The patients’ median overall survival (OS) and progression free survival (PFS) were 10.3 (95% confidence interval [CI], 8.5–12.1) and 6.5 (95% CI, 4.9–8.1) months, respectively. Patients with low sTGF-β at diagnosis ( < 31.2ng/mL) had better OS and PFS than patients with high sTGF-β, respectively (OS, 13.7 vs. 9.2 months; hazard ratio [HR], 2.602; P =0.004; PFS, 9.0 vs. 5.8 months; HR, 2.010; P =0.034). At the time of disease progression, sTGF-β was increased compared with that of diagnosis (mean 26.4 vs. 23.9ng/mL). Especially, in patients with a partial response, sTGF-β was significantly increased at disease progression (mean 25.7 vs. 31.0ng/mL; P =0.049). Conclusions: Pre-treatment sTGF-β levels serve as a prognostic indicator in unresectable pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Likewise, the dynamics of sTGF-β during chemotherapy have prognostic value.

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