scholarly journals Differential Expression of Polyamine Pathways in Human Pancreatic Tumor Progression and Effects of Polyamine Blockade on Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6391
Author(s):  
Sai Preethi Nakkina ◽  
Sarah B. Gitto ◽  
Veethika Pandey ◽  
Jignesh G. Parikh ◽  
Dirk Geerts ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Differential Expression ◽  
Pancreatic Tumor ◽  
Polyamine Metabolism ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
Mrna Levels ◽  
Pdac Patient ◽  
Patient Prognosis

Pancreatic cancer is the fourth leading cause of cancer death. Existing therapies only moderately improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The present study investigates the importance of the polyamine metabolism in the pancreatic tumor microenvironment. Relative mRNA expression analysis identified differential expression of polyamine biosynthesis, homeostasis, and transport mediators in both pancreatic epithelial and stromal cells from low-grade pancreatic intraepithelial neoplasia (PanIN-1) or primary PDAC patient samples. We found dysregulated mRNA levels that encode for proteins associated with the polyamine pathway of PDAC tumors compared to early lesions. Next, bioinformatic databases were used to assess expression of select genes involved in polyamine metabolism and their impact on patient survival. Higher expression of pro-polyamine genes was associated with poor patient prognosis, supporting the use of a polyamine blockade therapy (PBT) strategy for inhibiting pancreatic tumor progression. Moreover, PBT treatment of syngeneic mice injected intra-pancreatic with PAN 02 tumor cells resulted in increased survival and decreased tumor weights of PDAC-bearing mice. Histological assessment of PBT-treated tumors revealed macrophage presence and significantly increased expression of CD86, a T cell co-stimulatory marker. Collectively, therapies which target polyamine metabolism can be used to disrupt tumor progression, modulate tumor microenvironment, and extend overall survival.

Modulation of the RANK/RANKL/OPG system and FOXP3+ regulatory T cells in the tumor microenvironment of noninvasive bladder cancer after intravesical oncotherad immunotherapy associated with platelet-rich plasma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 462-462
Author(s):  
Bianca Ribeiro de Souza Sasaki ◽  
Ianny Brum Reis ◽  
Gabriela Oliveira ◽  
Nelson Duran ◽  
Wagner José Fávaro
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Regulatory T Cells ◽  
Tumor Progression ◽  
Platelet Rich Plasma ◽  
Low Grade ◽  
Antitumor Effects ◽  
Cancer Group ◽  
Muscle Invasive

462 Background: The activity of the receptor activator of nuclear factor-kβ RANK/RANKL in cancer cells has been correlated with tumor progression and poor prognosis in solid tumors including bladder cancer. Regulatory T cells (Tregs), often identified by FOXP3 biomarker, suppress the anti-tumor response and allow immune tolerance through suppression of T cells. Immunomodulator OncoTherad is an inorganic phosphate nanocomplex associated with glycosidic protein, developed by the University of Campinas/Brazil, with antitumor effects. Previous reports have demonstrated immune activation and antitumor effects of Platelet Rich Plasma (PRP). We evaluated the effects of OncoTherad associated with PRP in the RANK/RANKL system and Tregs in a mouse model of non-muscle invasive bladder cancer (NMIBC). Methods: C57BL/6J mice were assigned to groups (n = 42): Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50 mg/ml); PRP (0.1 ml); OncoTherad (20 mg/ml); OncoTherad+PRP 10 mg/ml and OncoTherad+PRP 20 mg/ml. The intravesical doses (0.1 ml) were instilled once a week for 6 consecutive weeks after induction. Results: After NMIBC induction, all animals in the Cancer group showed flat carcinoma in situ (pTis) and both percentages of RANK, RANKL, OPG, and FOXP3 positive cells and the intensity of immunoreaction for these antigens were significantly higher in comparison with healthy animals. In addition to ensuring this NMIBC model, these results indicated the involvement of RANK/RANKL in urothelial carcinogenesis and the presence of Tregs in a suppressed immune tumor microenvironment. Mice treated with PRP only showed a 28.6% rate of tumor progression inhibition (TPI) and exhibited papillary urothelial carcinoma (pTa) and pTis. In this group, the intensity of the RANKL and FOXP3 immunoreaction was weaker when compared to the Cancer group. Thus, PRP showed immunomodulatory effects, reducing Tregs that are sources of RANKL. Oncotherad immunotherapy led to an TPI of 85.7%, and benign flat hyperplasia was the most frequent diagnosis. Oncotherad reduced the total RANK and RANKL immunoreactivities and decreased the intensity of RANKL immunostaining in comparison to the Cancer. In the OncoTherad+PRP 10 mg/ml or 20 mg/ml group, TPI was 71.4%, with a predominance of non-malignant lesions such as flat hyperplasia, low-grade intraurothelial neoplasia, and reactive atypia. Treatments with Oncotherad and Oncotherad plus PRP decreased the percentage of FOXP3+ cells and reduced the intensity of FOXP3 immunoreaction compared to the Cancer and PRP groups. Conclusions: The tumor inhibition obtained with Oncotherad plus PRP was related to the alteration of the immune profile of the tumor microenvironment by decreasing RANK/RANKL expression and Tregs, resulting in an effective immune response against the tumor.

scholarly journals Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

2021 ◽  
Vol 22 (24) ◽  
pp. 13408
Author(s):  
Utpreksha Vaish ◽  
Tejeshwar Jain ◽  
Abhi C. Are ◽  
Vikas Dudeja
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tumor ◽  
Therapeutic Strategies ◽  
Ductal Adenocarcinoma ◽  
Western World ◽  
Significant Heterogeneity ◽  
Cancer Associated Fibroblasts ◽  
Term Survival

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.

scholarly journals Expression of Hypoxia-Inducible Factors in Different Stages of Pancreatic Tumor Progression

Reports ◽  
2020 ◽  
Vol 3 (4) ◽  
pp. 30
Author(s):  
Jung Hwa Jung ◽  
Danuta Sosnowska ◽  
Jessica Weaver ◽  
Henri K. Parson ◽  
Carolina M. Casellini ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Pancreatic Tumor ◽  
Critical Role ◽  
Intraepithelial Neoplasia ◽  
Histochemical Staining ◽  
Ductal Adenocarcinoma ◽  
Novel Therapies ◽  
Hypoxia Inducible Factors ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Mucinous Neoplasm

Background: Early diagnosis in pancreatic cancer is key for improving prognosis. Hypoxia plays a critical role in tumor progression. Thus, an evaluation of associations between pancreatic tumor progression and markers of hypoxia is needed. Methods: We assessed the expression of hypoxia-inducible factors (HIF-1α and HIF-2α) by immuno-histochemical staining from 29 subjects with the following: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), and pancreatic ductal adenocarcinoma (PDAC) and compared it to the expression in non-tumor samples. Results: Expression of HIF-1α increased significantly from PanIN (3.01 ± 0.17) to IPMN (7.63 ± 0.18), NET (9.10 ± 0.23) and PDAC samples (11.06 ± 0.15, p < 0.0001). Similar findings were observed for HIF-2α (p < 0.0001)}. A strong correlation between HIF-1α and HIF-2α expression was demonstrated (R2 = 0.8408, p < 0.0001). Conclusions: This data suggest that HIF-1α and HIF-2α may play a role in the progression from PanIN through PDAC. Further studies are necessary to confirm these findings and determine the effect of HIFs abrogation on tumor progression that can lead to novel therapies.

scholarly journals Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Therapeutic Opportunities and Clinical Challenges

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2860
Author(s):  
Ashleigh R. Poh ◽  
Matthias Ernst
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Pancreatic Tumor ◽  
Treatment Modalities ◽  
Ductal Adenocarcinoma ◽  
Increased Risk ◽  
Clinical Models ◽  
Risk Of Disease ◽  
Macrophage Targeting

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of less than 10%. Macrophages are one of the earliest infiltrating cells in the pancreatic tumor microenvironment, and are associated with an increased risk of disease progression, recurrence, metastasis, and shorter overall survival. Pre-clinical studies have demonstrated an unequivocal role of macrophages in PDAC by contributing to chronic inflammation, cancer cell stemness, desmoplasia, immune suppression, angiogenesis, invasion, metastasis, and drug resistance. Several macrophage-targeting therapies have also been investigated in pre-clinical models, and include macrophage depletion, inhibiting macrophage recruitment, and macrophage reprogramming. However, the effectiveness of these drugs in pre-clinical models has not always translated into clinical trials. In this review, we discuss the molecular mechanisms that underpin macrophage heterogeneity within the pancreatic tumor microenvironment, and examine the contribution of macrophages at various stages of PDAC progression. We also provide a comprehensive update of macrophage-targeting therapies that are currently undergoing clinical evaluation, and discuss clinical challenges associated with these treatment modalities in human PDAC patients.

scholarly journals TGFβ Signaling in the Pancreatic Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5086
Author(s):  
Daniel R. Principe ◽  
Kaytlin E. Timbers ◽  
Luke G. Atia ◽  
Regina M. Koch ◽  
Ajay Rana
Keyword(s):  
Tumor Microenvironment ◽  
Epithelial To Mesenchymal Transition ◽  
Pancreatic Tumor ◽  
Transforming Growth Factor ◽  
Immune Surveillance ◽  
Transforming Growth Factor Β ◽  
Ductal Adenocarcinoma ◽  
Surveillance Program ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients.

scholarly journals Neutrophil in the Pancreatic Tumor Microenvironment

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1170
Author(s):  
Lin Jin ◽  
Hong Sun Kim ◽  
Jiaqi Shi
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Pancreatic Tumor ◽  
Survival Rates ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Therapeutic Implications ◽  
Tumor Lesion

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells in the PDAC microenvironment. Recent studies have identified several cellular mechanisms by which neutrophils are recruited to tumor lesion and promote tumorigenesis. This review summarizes the current understanding of the interplay between neutrophils, tumor cells, and other components in the PDAC tumor microenvironment. The prognosis and therapeutic implications of neutrophils in PDAC are also discussed.

The Physical Microenvironment of Tumors: Characterization and Clinical Impact

2020 ◽  
Vol 15 (02) ◽  
pp. 51-82
Author(s):  
Matthew R. Zanotelli ◽  
Neil C. Chada ◽  
C. Andrew Johnson ◽  
Cynthia A. Reinhart-King
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Critical Role ◽  
Clinical Impact ◽  
Cancer Type ◽  
Wide Range ◽  
Patient Prognosis ◽  
Physical Features

The tumor microenvironment plays a critical role in tumorigenesis and metastasis. As tightly controlled extracellular matrix homeostasis is lost during tumor progression, a dysregulated extracellular matrix can significantly alter cellular phenotype and drive malignancy. Altered physical properties of the tumor microenvironment alter cancer cell behavior, limit delivery and efficacy of therapies, and correlate with tumorigenesis and patient prognosis. The physical features of the extracellular matrix during tumor progression have been characterized; however, a wide range of methods have been used between studies and cancer types resulting in a large range of reported values. Here, we discuss the significant mechanical and structural properties of the tumor microenvironment, summarizing their reported values and clinical impact across cancer type and grade. We attempt to integrate the values in the literature to identify sources of reported differences and commonalities to better understand how aberrant extracellular matrix dynamics contribute to cancer progression. An intimate understanding of altered matrix properties during malignant transformation will be crucial in effectively detecting, monitoring, and treating cancer.

scholarly journals Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

2021 ◽  
Author(s):  
Yanqing Huang ◽  
Carolina J. Garcia Garcia ◽  
Daniel Lin ◽  
Nicholas D. Nguyen ◽  
Tara N. Fujimoto ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Immune Checkpoint ◽  
Cellular Response ◽  
Ex Vivo ◽  
Smooth Muscle Actin ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors

Background & Aims. Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. Methods. We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin (αSMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF-Hif2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. Results. CAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. Conclusions. Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.

Sign in / Sign up

Export Citation Format

Share Document