Figure 1 - uploaded by Christine Feig
Content may be subject to copyright.
H&E stain of human pancreatic ductal adenocarcinoma showing a prominent desmoplastic reaction (black arrows), neoplastic ductal cells (arrows) and inflammatory cells (white arrows).
Source publication
Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation i...
Citations
... Despite optimism for newer chemotherapeutics and neoadjuvant therapy for downstaging PDAC, their efficacy in overall survival remains limited for patients with unresectable tumors [85]. One major challenge is the poor penetration of systemic chemotherapy due to tumor desmoplasia [85,86]. Intratumoral chemotherapy or stromal disrupting agents might offer a solution, as they can achieve higher drug concentrations within the tumor compared to systemic administration [85]. ...
Pancreatic cancer is on the rise and expected to become the second leading cause of cancer-related death by 2030. Up to a one-fifth of pancreatic cancers may arise from mucinous pancreatic cysts, which are frequently present in the general population. Currently, surgical resection is the only curative approach for pancreatic cancer and its cystic precursors. However, only a dismal proportion of patients are eligible for surgery. Therefore, novel treatment approaches to treat pancreatic cancer and precancerous pancreatic cysts are needed. Endoscopic ultrasound (EUS)-guided ablation is an emerging minimally invasive method to treat pancreatic cancer and premalignant pancreatic cysts. Different ablative modalities have been used including alcohol, chemotherapy agents, and radiofrequency ablation. Cumulative data over the past two decades have shown that endoscopic ablation of mucinous pancreatic cysts can lead to cyst resolution in a significant proportion of the treated cysts. Furthermore, novel data are emerging about the ability to endoscopically ablate early and locally advanced pancreatic cancer. In this review, we aim to summarize the available data on the efficacy and safety of the different EUS-ablation modalities for the management of premalignant pancreatic cysts and pancreatic cancer.
... Gemcitabine (GEM; 2′,2′-difluoro-2′-deoxycytidine), a pyrimidine nucleoside analogue renowned for its capacity to induce DNA damage, apoptosis, and cell cycle perturbation, has long held the mantle as the first-line chemotherapy agent for locally advanced and metastatic PC [5][6][7]. However, the efficacy of GEM is compromised by the inherent propensity of PC cells to develop resistance, a phenomenon exacerbated by the inadequate penetration and delivery of drugs through the dense and poorly vascularized tumor stroma [8]. This acquisition of GEM resistance stands as a significant barrier to improving patient outcomes in clinical practice, thereby accentuating the urgent need to surmount this hurdle. ...
... Tumor cells and stromal cells engage in metabolic signaling to prioritize cancer cells for glucose utilization during the scarcity of nutrients. Stromal cell metabolism has been relatively underexplored, despite their prevalence in tumors, accounting for as much as 80-90% in desmoplastic pancreatic cancer [103,104]. Cancer cells with various phenotypes use various energy sources through multiple metabolic pathways. Hypoxic cancer/stromal cells (e.g., CAFs) express higher levels of GLUT1 and utilize transported glucose for lactate production. ...
Cellular plasticity and therapy resistance are critical features of pancreatic cancer, a highly aggressive and fatal disease. The pancreas, a vital organ that produces digestive enzymes and hormones, is often affected by two main types of cancer: the pre-dominant ductal adenocarcinoma and the less common neuroendocrine tumors. These cancers are difficult to treat due to their complex biology characterized by cellular plasticity leading to therapy resistance. Cellular plasticity refers to the capability of cancer cells to change and adapt to different microenvironments within the body which includes acinar-ductal metaplasia, epithelial to mesenchymal/epigenetic/metabolic plasticity, as well as stemness. This plasticity allows heterogeneity of cancer cells, metastasis, and evasion of host’s immune system and develops resistance to radiation, chemotherapy, and targeted therapy. To overcome this resistance, extensive research is ongoing exploring the intrinsic and extrinsic factors through cellular reprogramming, chemosensitization, targeting metabolic, key survival pathways, etc. In this review, we discussed the mechanisms of cellular plasticity involving cellular adaptation and tumor microenvironment and provided a comprehensive understanding of its role in therapy resistance and ways to overcome it.
... 44,45 For certain types of cancer, such as pancreatic and prostate cancer, this stroma can constitute up to 90% of the overall tumor volume. [45][46][47][48][49] The densely packed stromal tissue can greatly impact tumor growth and drug response, occurring hypoxia and abnormal tumor vasculature. Thus, tumor MPS capable of recapitulating the complex features of TME is crucial to better model the human system, understand physiological processes, facilitate the targeting of drug discovery, and provide a faithful replication of physiological condition for drug transport. ...
Microphysiological systems (MPSs), also known as organ-on-chip or disease-on-chip, have recently emerged to reconstitute the in vivo cellular microenvironment of various organs and diseases on in vitro platforms. These microfluidics-based platforms are developed to provide reliable drug discovery and regulatory evaluation testbeds. Despite recent emergences and advances of various MPS platforms, their adoption of drug discovery and evaluation processes still lags. This delay is mainly due to a lack of rigorous standards with reproducibility and reliability, and practical difficulties to be adopted in pharmaceutical research and industry settings. This review discusses the current and potential use of MPS platforms in drug discovery processes while considering the context of several key steps during drug discovery processes, including target identification and validation, preclinical evaluation, and clinical trials. Opportunities and challenges are also discussed for the broader dissemination and adoption of MPSs in various drug discovery and regulatory evaluation steps. Addressing these challenges will transform long and expensive drug discovery and evaluation processes into more efficient discovery, screening, and approval of innovative drugs.
... When the tumor morphology variation manifests in the macroscopic level, i.e., in the millimeter range, an effect can be observed in the ADC value and distribution. It is plausible that in the p16-tumors, a low mean ADC value or low peak ADC values of the two components indicate a low total percentage of stroma, and thereby less protection of tumor cells from CRT by stroma and better tumor control (27)(28)(29)(30)(31)(32). In the p16+ oropharynx tumors, tumor microstructure may be affected by tumor infiltrating lymphocytes (33, 34), where a large subvolume with low ADC in the tumor volume, low mean ADC or low µ L value, could need to be treated with high radiation doses to have an improved local and regional tumor control. ...
Purpose
To investigate p16 effects on diffusion image metrics and associations with tumor progression in patients with locally advanced head and neck cancers.
Methods
Diffusion images pretreatment and after 20 Gy (2wk) of RT were analyzed in patients with cT4/N3 p16+ oropharynx cancer (OPSCC) (N=51) and locoregionally advanced head and neck squamous cell carcinoma (LAHNSCC) (N=28), enrolled onto a prospective adaptive RT trial. Mean ADC values, subvolumes with ADC <1.2 um²/ms (TVLADC), and peak values of low (µL) and high (µH) components of ADC histograms in primary and total nodal gross tumor volumes were analyzed for prediction of freedom from local, distant, or any progression (FFLP, FFDP or FFLRDP) using multivariate Cox proportional-hazards model with clinical factors. P value with false discovery control <0.05 was considered as significant.
Results
With a mean follow up of 36 months, 18 of LAHNSCC patients and 16 of p16+ OPSCC patients had progression. After adjusting for p16, small µL and ADC values, and large TVLADC of primary tumors pre-RT were significantly associated with superior FFLRDP, FFLP and FFDP in the LAHNSCC (p<0.05), but no diffusion metrics were significant in p16+ oropharynx cancers. Post ad hoc analysis of the p16+ OPSCC only showed that large TVLADC of the total nodal burden pre-RT was significantly associated with inferior FFDP (p=0.05).
Conclusion
ADC metrics were associated with different progression patterns in the LAHNSCC and p16+ OPSCC, possibly explained by differences in cancer biology and morphology. A deep understanding of ADC metrics is warranted to establish imaging biomarkers for adaptive RT in HNSCC.
... PDAC develops through the preceding formation of acinar-to-duct metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), which are primarily driven by oncogenic Kras activation (2). In addition, PDAC is associated with an abundant stromal reaction that usually surrounds islands of cancer cells and accounts for 50-80% of the tumor volume (3,4). ...
... A broad range of extracellular matrix (ECM) proteins, such as collagens, fibrous and nonfibrous glycoproteins, and proteoglycans contribute to the structural formation of the noncellular stromal compartment. In addition, the ECM also contains nonstructural components, such as growth factors and matricellular proteins (4)(5)(6). The cellular compartment of the stroma includes immune cells, such as lymphocytes, macrophages, mast cells, and myeloid-derived suppressor cells (MDSCs), along with vascular and neural elements (endothelial cells and neurons, respectively) (7)(8)(9). ...
Pancreatic ductal adenocarcinoma (PDAC) is associated with a vast stromal reaction that arises mainly from cancer-associated fibroblasts (CAFs) and promotes both immune escape and tumor growth. Here, we used a mouse model with deletion of the activin A receptor ALK4 in the context of the KrasG12D mutation, which strongly drives collagen deposition that leads to tissue stiffness. By ligand–receptor analysis of single-cell RNA-sequencing data, we identified that, in stiff conditions, neoplastic ductal cells instructed CAFs through sustained platelet-derived growth factor (PDGF) signaling. Tumor-associated tissue rigidity resulted in the emergence of stiffness-induced CAFs (siCAFs) in vitro and in vivo. Similar results were confirmed in human data. siCAFs were able to strongly inhibit CD8+ T-cell responses in vitro and in vivo, promoting local immunosuppression. More importantly, targeting PDGF signaling led to diminished siCAF and reduced tumor growth. Our data show for the first time that early paracrine signaling leads to profound changes in tissue mechanics, impacting immune responses and tumor progression. Our study highlights that PDGF ligand neutralization can normalize the tissue architecture independent of the genetic background, indicating that finely tuned stromal therapy may open new therapeutic avenues in pancreatic cancer.
... Its lethality is supported by a lack of early-stage symptoms and a lack of effective treatment options at late metastasized stages (Gupta et al. 2021a,b). A dense immuno-suppressive tumor microenvironment, that makes up about 90% of the tumor volume, acts as a buffer to keep the immune system at bay (Neesse et al., 2011). The likelihood of medication resistance and tumor recurrence increases when such tumor microenvironment exists (Gupta & Tejavath, 2022). ...
With no prominent treatment for pancreatic ductal adenocarcinoma (PDAC) in conventional chemotherapy, recent studies have focused on uniting conventional and traditional medicines including plant phytoconstituents. Herein, we used pharmacoinformatic studies to identify potent phytoconstituent as ligand having inhibition activities against canonical anticancer targets, and evaluated its effect on PDAC cell lines. SwissTargetPrediction and SuperPred tools were utilized to segregate protein targets of ligand in humans, following which FunRich was applied to garner its targets in PDAC. STRING analysis predicted protein–protein interactions and dynamic simulation studies confirmed stability of ligand–protein complex. For in vitro cytotoxic potential, ligand treatment at different concentrations was given to PDAC cell lines both alone and combined with gemcitabine, followed by evaluation of effects on migration. Differential gene expression was checked using PCR for evaluating mechanism of cytotoxicity. Results showed pentagalloylglucose (PGG) with highest docking and MMGBSA scores for Cyclooxygenase 2 (Cox2) inhibition site. SwissTargetPrediction and SuperPred analysis detected 40 targets of PGG in PDAC. Simulation data showed stability of protein–ligand complex. In in vitro experiments Mia-PaCa-2 was more sensitive to PGG than Panc-1. PGG successfully inhibited migration both alone and in combination with gemcitabine. Additionally, PGG treatment induced apoptosis in both the cell lines; but showed antagonism when combined with gemcitabine. In conclusion, our report demonstrates PGG has good binding with Cox2 and showed anti-PDAC activity by inhibiting migration and inducing apoptosis, thus it can be used as a therapy option. But further studies are required to confirm its behaviour as a combination therapy drug.
Communicated by Ramaswamy H. Sarma
... In pancreatic cancer, the extensive desmoplastic reaction leads to the formation of a dense stroma, causing inadequate vascularisation, inefficient drug delivery, and ineffective immune cell infiltration into the tumour sites, which eventually leads to therapeutical resistance and cancer progression [93]. PAKs have been recognised for their roles in the regulation of vasculature and therapeutical response. ...
Angiogenesis has been associated with numbers of solid tumours. Anti-angiogenesis drugs starve tumours of nutrients and oxygen but also make it difficult for a chemo reagent to distribute into a tumour, leading to aggressive tumour growth. Anti-angiogenesis drugs do not appear to improve the overall survival rate of pancreatic cancer. Vessel normalisation is merging as one of the new approaches for halting tumour progression by facilitating the tumour infiltration of immune cells and the delivery of chemo reagents. Targeting p21-activated kinases (PAKs) in cancer has been shown to inhibit cancer cell growth and improve the efficacy of chemotherapy. Inhibition of PAK enhances anti-tumour immunity and stimulates the efficacy of immune checkpoint blockades. Inhibition of PAK also improves Car-T immunotherapy by reprogramming the vascular microenvironment. This review summarizes current research on PAK’s role in tumour vasculature and therapeutical response, with a focus on pancreatic cancer.
... Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a highly desmoplastic microenvironment comprising abundant stromal cells and extracellular matrix (1). This produces a high interstitial fluid pressure that restricts blood flow within the tumor parenchyma, limiting drug delivery while also inducing extreme hypoxia (2)(3)(4). ...
The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.
Significance
We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment.
... The GemPred signature takes into account the expression of more than 2,000 genes whose combination was shown to correlate with the RNA expression of hENT1 and of the cytidine deaminase gene CDA 13 but not dCK. A more comprehensive integration of gemcitabine metabolism genes, 10 putative genetic signatures, 20 stromal signatures, 21 and transcriptome deconvolution 22 may be considered to improve the signature. It would also be of interest to combine GemPred with other predictive biomarkers, in particular, BRCA-related alterations, which suggests a benefit from platinum-base regimens, 23 especially at the metastatic stage. ...
PURPOSE
GemPred, a transcriptomic signature predictive of the efficacy of adjuvant gemcitabine (GEM), was developed from cell lines and organoids and validated retrospectively. The phase III PRODIGE-24/CCTG PA6 trial has demonstrated the superiority of modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX) over GEM as adjuvant therapy in patients with resected pancreatic ductal adenocarcinoma at the expense of higher toxicity. We evaluated the potential predictive value of GemPred in this population.
PATIENTS AND METHODS
Routine formalin-fixed paraffin-embedded surgical specimens of 350 patients were retrieved for RNA sequencing and GemPred prediction (167 in the GEM arm and 183 in the mFOLFIRINOX [mFFX] arm). Survival analyses were stratified by resection margins, lymph node status, and cancer antigen 19-9 level.
RESULTS
Eighty-nine patients' tumors (25.5%) were GemPred+ and were thus predicted to be gemcitabine-sensitive. In the GEM arm, GemPred+ patients (n = 50, 30%) had a significantly longer disease-free survival (DFS) than GemPred– patients (n = 117, 70%; median 27.3 v 10.2 months, hazard ratio [HR], 0.43 [95% CI, 0.29 to 0.65]; P < .001) and cancer-specific survival (CSS; median 68.4 v 28.6 months, HR, 0.42 [95% CI, 0.27 to 0.66]; P < .001). GemPred had no prognostic value in the mFFX arm. DFS and CSS were similar in GemPred+ patients who received adjuvant GEM and mFFX (median 27.3 v 24.0 months, and 68.4 v 51.4 months, respectively). The statistical interaction between GEM and GemPred+ status was significant for DFS ( P = .008) and CSS ( P = .004). GemPred+ patients had significantly more adverse events of grade ≥3 in the mFFX arm (76%) compared with those in the GEM arm (40%; P = .001).
CONCLUSION
This ancillary study of a phase III randomized trial demonstrates that among the quarter of patients with a GemPred-positive transcriptomic signature, survival was comparable with that of mFOLFIRINOX, whereas those receiving adjuvant gemcitabine had fewer adverse events.
