Pancreatic Cancer-Secreted Proteins in Tumor Microenvironment: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Alessandra Rosati.

Pancreatic Ductal Adenocarcinoma (PDAC) is a ravaging disease with a poor prognosis, requiring a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggest a shift in focus towards the tumor microenvironment (TME). Here, we discuss tThe role of cancer-secreted proteins in the complex TME tumor-stroma crosstalk, shedding lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies is discussed here.

  • pancreatic ductal adenocarcinoma
  • secretome
  • cell signaling
  • tumor microenvironment
  • small molecules

1. Pancreatic Cancer Fact Sheet

The most common type of pancreatic cancer is the Pancreatic Ductal Adenocarcinoma (PDAC), which arises from the ductal epithelium of the organ. Around 70% of pancreatic cancers begin in the organ’s head, with the majority starting from the ducts that transport digestive enzymes [1,2][1][2]. The prevalence rate is 49.8 cases per million people, while the predicted global incidence rate is 58.6 cases per million people annually. Annual mortality is projected to be 57.7 per million persons. Over the past 25 years, there has been a 55%, 63% and 53% increase of the incidence, prevalence and death rates, respectively. While representing only 1.8% of all malignancies, pancreatic cancer is responsible for 4.6% of cancer-related fatalities. Men have a somewhat greater incidence, prevalence, and fatality rate. By 2060, it is anticipated that pancreatic cancer deaths would have increased almost 1.97-fold [3].
Despite recent advances in surgical techniques and medical therapies, the median survival time for a pancreatic cancer patient at the time of diagnosis is 4–6 months, with a 12% five-year survival rate [3,4][3][4]. Pancreatic cancer is predicted to become the second leading cause of cancer-related deaths in the United States by 2030, surpassing colorectal, breast, and prostate cancer. Moreover, it has been reported that by 2040, gastrointestinal cancers (pancreatic, liver, and colorectal cancer) are expected to be three of the four leading causes of cancer death [5].
The main reasons for such a poor prognosis can be attributed to the particularly complex anatomical region in which the tumor grows, as well as the fact that this tumor is usually diagnosed at an advanced stage in most patients.
The early stage and onset of the disease are characterized by rather vague disorders, which are often clinically misinterpreted, leading to delays in diagnosis until a stage marked by its fatal spread. The survival rate of patients dramatically drops in the first year after the diagnosis. Unfortunately, significant improvements in therapeutic protocols for this neoplasm have not been developed in the last three decades, resulting in a uniformly poor prognosis worldwide [5,6][5][6]. The only potentially curative treatment is surgical removal, but radical surgical resection of the tumor is indicated only in cases of intrapancreatic disease that does not extend to the retroperitoneum or transverse mesocolon and does not involve infiltration of the superior mesenteric artery, celiac tripod, or spleno-mesenteric-portal axis. For this reason, pancreatic cancer is only resectable in 10–20% of patients at the time of diagnosis, while it is locally advanced in 30–35% of patients due to infiltration of the large abdominal vessels, and metastases are already present in more than 50% of cases. However, even in the early stages, the prognosis is poor, with median survival rates with surgery alone in this group of patients being in the order of 12 months, and the five-year survival rate is between 5 and 10%. Median survival for stages III and IV is 10 and 6 months, respectively [7,8][7][8].

2. Proteins Secreted by Pancreatic Cancer Cells: Messages Sent to the Neighborhood

Cell communication in multicellular organisms allows cells to adapt their phenotypes and function. A number of secreted factors, whether soluble or associated with membranes, mediate critical molecular mechanisms involved in tissue and organism homeostasis. Typically, proteins follow the conventional protein secretion pathway, which involves the endoplasmic reticulum (ER) and the Golgi complex. However, some proteins use alternative routes, such as Unconventional Protein Secretion (UPS) pathways, induced by cellular stress such as nutrient deficiency, mechanical stress, inflammation, and ER stress. When the pathways leading to protein secretion, mediating both short- and long-range signals, are dysregulated, it accelerates disease pathogenesis. In addition, for some cancers, there is growing interest in intracellular proteins that, if secreted, play distinct functions, demonstrating that UPS pathways are still not fully understood [32][9]. In this context, tumor secretomes are able to influence the behavior of both neoplastic and non- neoplastic cells, providing a promising source of potential biomarkers useful in patient management. In fact, the alteration of the secretome mirrors disrupted cell-cell signaling in the pancreatic cancer milieu and participated in the reshaping of a fibrotic and inflammatory micro-environment that promotes cancer development and progression [33][10]. The obtained dataset represented and summarized the coexistence of cytokines, growth factors, extracellular matrix proteins, proteases and protease inhibitors, membrane and extracellular vesicle-associated proteins, and metabolic enzymes in the neoplastic milieu (Figure 1). Enzymes accounted for 32% of the proteins reported in the study, whereas enzyme inhibitors accounted for 5%. Cell signaling molecules accounted for 19%, while specific cell-matrix adhesion molecules accounted for 20%. Proteins with multiple roles accounted for 19% of the studied dataset, with the remaining 5% representing gene expression regulators and 6% representing transporters.

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Figure 1. Proteins Functions—A Global Core Biodata Resource, Panther Classification System (https://pantherdb.org/, accessed on 11 June 2023), classified the gene dataset for functions. Proteins secreted by pancreatic cancer cells were classified as having a general function (left column) or a specific function (right column). An Alluvial plot (https://www.mapequation.org/alluvial/, accessed on 28 June 2023) was used to depict the classifications. Furthermore, percentages of secreted proteins having common general functions are reported in the left column. A color code was used for each general function. In the column, the most represented protein functions are in the plot’s lower part.
To define protein clusters associated with main cellular processes, the dataset was analyzed in the GO biological processes 2023 database using Enrichr (https://appyters.maayanlab.cloud/, accessed on 7 June 2023) (Table 21).
Table 21. Clustered functions for pancreatic cancer-secreted proteins—Enrichr-Appyter online applications generated a downloadable table. The names of the genes were reported along with the p-values and q-values of significant terms in the chosen library. The q-value is an adjusted p-value calculated using the Benjamini-Hochberg method for multiple hypothesis testing correction.
Term p-Value q-Value Overlaps Genes
Extracellular Matrix Disassembly (GO:0022617) 7.05 × 10−9 2.09 × 10−6 [MMP12, PRSS1, GSN, MMP7, MMP2, MMP9, MMP10]
Regulation of Apoptotic Process (GO:0042981) 2.42 × 10−11 3.59 × 10−8 [HSP90AA1, GSTP1, ANXA5, PARK7, IGF1, CLU, MMP9, THBS1, ACTB, NME1, LGALS1, AXL, BAG3, CEACAM5, ARHGDIA, CFL1, ALB, PPT1, FLNA, CALR, PPIA, CTSD, TGM2]
Neutrophil Chemotaxis (GO:0030593) 1.94 × 10−7 2.88 × 10−5 [LGALS3, CCL24, CXCL8, SAA1, PPBP, PPIA, PF4]
Carbohydrate Catabolic Process (GO:0016052) 4.19 × 10−9 1.56 × 10−6 [LDHA, TPI1, PKM, PGAM1, PGK1, ENO1, ENO2]

As a result of the analysis, it was possible to highlight a set of proteases responsible for extracellular matrix and cellular component disassembly. As previously reported, the acellular components of the pancreatic tumor mass, as well as their changes over time, drive the tumor’s progression. In this regard, MMP-2 and MMP-9 (Matrix MetalloProteinases) gelatinases are abnormally and contemporarily upregulated in pancreatic cancer [48][11], but the clinical relevance measured by the correlation between their expression and survival, metastasis, or tumor stage is debatable [49][12]. Instead, the expression of the matrilysin MMP-7 in tumor samples was linked to a poorer prognosis in patients [50][13] and an unfavorable pathologic response to neoadjuvant therapy [51][14].

Some apoptosis-regulating proteins with very different biochemical functions have also been identified, and some of them have been linked to a role in pancreatic cancer. For example, Hsp90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1) is one of the most abundant proteins expressed in cells, interacting with several secreted client proteins. Hsp90AA1 promotes tumor aggressiveness and chemoresistance by activating AKT through LRP-1 (Low-density lipoprotein Receptor-related Protein 1) [54][15]. Among other chaperones, PARK7 (Parkinson protein 7) [55][16] and PPIA (Peptidylprolyl Isomerase A) [42][17] are upregulated and secreted by cancer cells. While PARK7 has been described for its ability to counteract environmental oxidative stress [56][18], PPIA is known to act through the CD47 and NF-kB pathway, thus promoting cell proliferation [57][19]. In addition, the extracellular chaperone Clusterin (CLU) has been shown to be a mediator of chemoresistance in pancreatic cancer [58][20]. The overexpression of the co-chaperone BAG3 (BCL2 Associated Athanogene 3) has also been described as associated with pancreatic cancer aggressiveness [59][21], and its sera levels are measurable in pancreatic cancer patients [45,60][22][23].

An additional functional cluster of secreted proteins was linked to neutrophil chemotaxis. Tumor-infiltrating neutrophils indicate a poor prognosis for patients, and activated neutrophils can generate neutrophil extracellular traps (NETs), which are emerging in several cancers as markers of cancer progression and immunosuppression [71,72][24][25]. As a first example, extracellular Galectin-3 (LGALS3), detected in the blood of PDAC patients [73][26], has been associated with neutrophils recruitment and inflammation exacerbation in several infectious diseases [74][27].

Moreover, altered carbohydrate catabolism has been recognized as the major metabolic alteration in pancreatic cancer [81][28], but the role of those enzymes in the pancreatic cancer milieu has not been fully elucidated yet. The evidence that secretory PKM (Pyruvate Kinase M1/2) promotes tumor angiogenesis by facilitating endothelial cell proliferation and new vessel formation via the PI3K/AKT and Wnt/-catenin signaling pathways provides some hints [82][29]. 

3. Targeting Pancreatic Cancer-Secreted Proteins

3.1. Communications Breakdown Operated by Small Molecule Drugs

The DGIdb (The Drug Gene Interaction Database, accessed on 28 June 2023) was queried, screened and integrated with a literature search for available molecules possibly having inhibitory activity on pancreatic cancer-secreted proteins illustrated above; the obtained search results are described below. The response to synthetic inhibitors of MMPs (MMPIs) was studied in the past decades in several solid tumors. However, despite promising preclinical data, all trials were unsuccessful in reducing tumor mass or improving overall survival [89][30]. Clusterin expression was challenged using the drug OGX-011, an antisense oligonucleotide that showed a potentiating effect on various FDA-approved anticancer chemotherapeutics during clinical trials [90][31]; however, no trial in pancreatic cancer has been programmed yet [91][32]. Ganetespib (STA-9090) is a small molecule that interferes with HSP90 client protein binding, thus promoting the inactivation and degradation of the signaling proteins that regulate cancer progression. Unfortunately, a Phase II study carried out in refractory metastatic pancreatic cancer failed to prove its clinical efficacy [92][33]. More clinical trials as a neoadjuvant treatment and/or in combination with chemotherapy are expected [93][34].

3.2. Communications Breakdown Operated by Monoclonal Antibodies

The target specificity of monoclonal antibodies (mAbs) makes them powerful tools for a wide spectrum of biomedical and clinical application. As previously stated, the use of DGIdb was supported and integrated by a literature search to identify available mAbs able to bind and neutralize the secreted proteins here selected for discussion. Xentuzumab, an IgG1 monoclonal antibody with high affinity for IGF-1 and IGF-2 currently tested in preclinical models for the treatment of advanced solid tumors, allowed the collection of several interesting data [96,97][35][36]. A phase I trial enrolling patients affected by different advanced solid tumors, including PDAC, allowed verifying its safety, tolerability, and clinical manageability. On the other hand, in a phase II study in metastatic breast cancer, treatments with Xentuzumab combined with everolimus and exemestane did not show a significant impact on PFS (Progression Free Survival) [98][37]. Another strategy, aimed at neutralizing VEGF with the monoclonal antibody Bevacizumab, showed promising results in preclinical studies [99][38], but it did not show appreciable benefits when combined with gemcitabine in clinical trials [100][39]. Thanks to its high safety profile, trials were further extended to a third compound, erlotinib, but still without satisfying results [101][40]. In this context, the neutralization of extracellular BAG3 is another promising strategy supported by studies carried out in several murine preclinical models treated with an anti-BAG3 mAb, which showed its ability in reducing PDAC tumor growth as monotherapy [61,104][41][42]. But even more striking results were observed in combined treatments with the ICIs (Immune Check-point Inhibitors) anti-PD-1 [105][43] and anti-SIRP-alpha [106][44]. An anti-IL-8 antibody was also tested in a humanized mouse model of PDAC in combination with anti-PD-1. The treatment resulted in significantly reduced tumor growth, as well as an increased innate immune response and type I cytokine expression in myeloid cells, revealing a novel function of the IL-8 antibody in myeloid cell “re-education” [109][45]. HuMax-IL8 was tested in a Phase I trial on solid tumors, showing its safety and tolerability, while further studies are ongoing to evaluate the efficacy of anti-IL-8 treatments combined with other immunotherapies [110][46]. Another strategic perspective aims at targeting the asTF protein by a first-in-class humanized antibody, which exerted a significant effect on tumor growth in an animal model, downregulating several gene function categories, including focal adhesion, cell motility, cell proliferation, cytoskeleton, regulatory proteases and cell death, many of which are known to be TF- associated [111][47]. In this case, XB002, a novel, investigational ADC (Antibody Drug Conjugate), is currently being tested as a single-agent and combination therapy in subjects with inoperable locally advanced, or metastatic solid tumors in a Phase I trial; results are expected in late 2024 (NCT04925284) (Figure 2).
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Figure 2. Druggable secreted proteins landscape in pancreatic cancer cells. Inhibition arrows were used for small molecule drugs. Image was realized using Biorender (https://app.biorender.com/, accessed on 7 June 2023).

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