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Nature Communications Apr 2023Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell...
Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here, we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favors a more permissive microenvironment, which accelerates the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via upregulation of tumor necrosis factor receptor 2 (TNFR2), promotes TNF-mediated upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. Extracellular HAPLN1 modifies cancer cells and fibroblasts, rendering them more immunomodulatory. As such, we identify HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC.
Topics: Mice; Animals; Peritoneum; Peritoneal Neoplasms; Hyaluronic Acid; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Neoplasm Metastasis; Gene Expression Regulation, Neoplastic; Tumor Microenvironment
PubMed: 37095087
DOI: 10.1038/s41467-023-38064-w -
Journal For Immunotherapy of Cancer Dec 2022The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade...
BACKGROUND
The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade (ICB). However, resistance to ICB is commonly observed, and is associated with the presence of peritoneal-metastases and ascites formation. The mechanisms underlying this site-specific benefit of ICB are unknown.
METHODS
We created a novel model for spontaneous multiorgan metastasis in MSI-H CRC tumors by transplanting patient-derived organoids (PDO) into the cecum of humanized mice. Anti-programmed cell death protein-1 (PD-1) and anti-cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) ICB treatment effects were analyzed in relation to the immune context of primary tumors, liver metastases, and peritoneal metastases. Immune profiling was performed by immunohistochemistry, flow cytometry and single-cell RNA sequencing. The role of B cells was assessed by antibody-mediated depletion. Immunosuppressive cytokine levels (interleukin (IL)-10, transforming growth factor (TGF)b1, TGFb2, TGFb3) were determined in ascites and serum samples by ELISA.
RESULTS
PDO-initiated primary tumors spontaneously metastasized to the liver and the peritoneum. Peritoneal-metastasis formation was accompanied by the accumulation of ascites. ICB completely cleared liver metastases and reduced primary tumor mass but had no effect on peritoneal metastases. This mimics clinical observations. After therapy discontinuation, primary tumor masses progressively decreased, but peritoneal metastases displayed unabated growth. Therapy efficacy correlated with the formation of tertiary lymphoid structures (TLS)-containing B cells and juxtaposed T cells-and with expression of an interferon-γ signature together with the B cell chemoattractant CXCL13. B cell depletion prevented liver-metastasis clearance by anti-CTLA-4 treatment. Peritoneal metastases were devoid of B cells and TLS, while the T cells in these lesions displayed a dysfunctional phenotype. Ascites samples from patients with cancer with peritoneal metastases and from the mouse model contained significantly higher levels of IL-10, TGFb1, TGFb2 and TGFb3 than serum samples.
CONCLUSIONS
By combining organoid and humanized mouse technologies, we present a novel model for spontaneous multiorgan metastasis by MSI-H CRC, in which the clinically observed organ site-dependent benefit of ICB is recapitulated. Moreover, we provide empirical evidence for a critical role for B cells in the generation of site-dependent antitumor immunity following anti-CTLA-4 treatment. High levels of immunosuppressive cytokines in ascites may underlie the observed resistance of peritoneal metastases to ICB.
Topics: Mice; Animals; Immune Checkpoint Inhibitors; Transforming Growth Factor beta3; Peritoneum; Ascites; Peritoneal Neoplasms; Cytokines; Liver Neoplasms; Colorectal Neoplasms
PubMed: 36543378
DOI: 10.1136/jitc-2022-005345 -
Nature Communications Aug 2022A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of...
A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity.
Topics: Colorectal Neoplasms; Humans; Neoplasms, Second Primary; Peritoneal Neoplasms; Peritoneum; Quality of Life
PubMed: 35927254
DOI: 10.1038/s41467-022-32198-z -
EBioMedicine Jun 2023Peritoneal metastasis is a challenging aspect of clinical practice for gastric cancer. Animal models are crucial in understanding molecular mechanisms, assessing drug... (Review)
Review
Peritoneal metastasis is a challenging aspect of clinical practice for gastric cancer. Animal models are crucial in understanding molecular mechanisms, assessing drug efficacy, and conducting clinical intervention studies, including those related to gastric cancer peritoneal metastasis. Unlike other xenograft models, peritoneal metastasis models should not only present tumor growth at the transplant site, but also recapitulate tumor cell metastasis in the abdominal cavity. Developing a reliable model of gastric cancer peritoneal metastasis involves several technical aspects, such as the selection of model animals, source of xenograft tumors, technology of transplantation, and dynamic monitoring of the tumor progression. To date, challenges remain in developing a reliable model that can completely recapitulate peritoneal metastasis. Thus, this review aims to summarize the techniques and strategies used to establish animal models of gastric cancer peritoneal metastasis, providing a reference for future model establishment.
Topics: Animals; Humans; Peritoneal Neoplasms; Stomach Neoplasms; Peritoneum; Transplantation, Heterologous; Heterografts; Cell Line, Tumor
PubMed: 37182268
DOI: 10.1016/j.ebiom.2023.104601 -
Peritoneal Dialysis International :... Jan 2021(1) Peritoneal dialysis (PD) should be considered a suitable modality for treatment of acute kidney injury (AKI) in all settings .
SUMMARY STATEMENTS
(1) Peritoneal dialysis (PD) should be considered a suitable modality for treatment of acute kidney injury (AKI) in all settings .
GUIDELINE 2: ACCESS AND FLUID DELIVERY FOR ACUTE PD IN ADULTS
(2.1) Flexible peritoneal catheters should be used where resources and expertise exist .(2.2) Rigid catheters and improvised catheters using nasogastric tubes and other cavity drainage catheters may be used in resource-poor environments where they may still be life-saving .(2.3) We recommend catheters should be tunnelled to reduce peritonitis and peri-catheter leak .(2.4) We recommend that the method of catheter implantation should be based on patient factors and locally available skills .(2.5) PD catheter implantation by appropriately trained nephrologists in patients without contraindications is safe and functional results equate to those inserted surgically .(2.6) Nephrologists should receive training and be permitted to insert PD catheters to ensure timely dialysis in the emergency setting (2.7) We recommend, when available, percutaneous catheter insertion by a nephrologist should include assessment with ultrasonography .(2.8) Insertion of PD catheter should take place under complete aseptic conditions using sterile technique .(2.9) We recommend the use of prophylactic antibiotics prior to PD catheter implantation .(2.10) A closed delivery system with a Y connection should be used . In resource poor areas, spiking of bags and makeshift connections may be necessary and can be considered .(2.11) The use of automated or manual PD exchanges are acceptable and this will be dependent on local availability and practices .
GUIDELINE 3: PERITONEAL DIALYSIS SOLUTIONS FOR ACUTE PD
(3.1) In patients who are critically ill, especially those with significant liver dysfunction and marked elevation of lactate levels, bicarbonate containing solutions should be used (. Where these solutions are not available, the use of lactate containing solutions is an alternative .(3.2) Commercially prepared solutions should be used . However, where resources do not permit this, then locally prepared fluids may be life-saving and with careful observation of sterile preparation procedure, peritonitis rates are not increased .(3.3) Once potassium levels in the serum fall below 4 mmol/L, potassium should be added to dialysate (using strict sterile technique to prevent infection) or alternatively oral or intravenous potassium should be given to maintain potassium levels at 4 mmol/L or above .(3.4) Potassium levels should be measured daily . Where these facilities do not exist, we recommend that after 24 h of successful dialysis, one consider adding potassium chloride to achieve a concentration of 4 mmol/L in the dialysate
GUIDELINE 4: PRESCRIBING AND ACHIEVING ADEQUATE CLEARANCE IN ACUTE PD
(4.1) Targeting a weekly / of 3.5 provides outcomes comparable to that of daily HD in critically ill patients; targeting higher doses does not improve outcomes . This dose may not be necessary for most patients with AKI and targeting a weekly / of 2.2 has been shown to be equivalent to higher doses . Tidal automated PD (APD) using 25 L with 70% tidal volume per 24 h shows equivalent survival to continuous venovenous haemodiafiltration with an effluent dose of 23 mL/kg/h .(4.2) Cycle times should be dictated by the clinical circumstances. Short cycle times (1-2 h) are likely to more rapidly correct uraemia, hyperkalaemia, fluid overload and/or metabolic acidosis; however, they may be increased to 4-6 hourly once the above are controlled to reduce costs and facilitate clearance of larger sized solutes .(4.3) The concentration of dextrose should be increased and cycle time reduced to 2 hourly when fluid overload is evident. Once the patient is euvolemic, the dextrose concentration and cycle time should be adjusted to ensure a neutral fluid balance .(4.4) Where resources permit, creatinine, urea, potassium and bicarbonate levels should be measured daily; 24 h / and creatinine clearance measurement is recommended to assess adequacy when clinically indicated .(4.5) Interruption of dialysis should be considered once the patient is passing >1 L of urine/24 h and there is a spontaneous reduction in creatinine .
UNLABELLED
The use of peritoneal dialysis (PD) to treat patients with acute kidney injury (AKI) has become more popular among clinicians following evidence of similar outcomes when compared with other extracorporeal therapies. Although it has been extensively used in low-resource environments for many years, there is now a renewed interest in the use of PD to manage patients with AKI (including patients in intensive care units) in higher income countries. Here we present the update of the International Society for Peritoneal Dialysis guidelines for PD in AKI. These guidelines extensively review the available literature and present updated recommendations regarding peritoneal access, dialysis solutions and prescription of dialysis with revised targets of solute clearance.
Topics: Acute Kidney Injury; Adult; Dialysis Solutions; Humans; Peritoneal Dialysis; Peritoneum; Peritonitis
PubMed: 33267747
DOI: 10.1177/0896860820970834 -
Korean Journal of Radiology Apr 2021The perihepatic space is frequently involved in a spectrum of diseases, including intrahepatic lesions extending to the liver capsule and disease conditions involving... (Review)
Review
The perihepatic space is frequently involved in a spectrum of diseases, including intrahepatic lesions extending to the liver capsule and disease conditions involving adjacent organs extending to the perihepatic space or spreading thanks to the communication from intraperitoneal or extraperitoneal sites through the hepatic ligaments. Lesions resulting from the dissemination of peritoneal processes may also affect the perihepatic space. Here we discuss how to assess the perihepatic origin of a lesion and describe the magnetic resonance imaging (MRI) features of normal structures and fluids that may be abnormally located in the perihepatic space. We then review and illustrate the MRI findings present in cases of perihepatic infectious, tumor-related, and miscellaneous conditions. Finally, we highlight the value of MRI over computed tomography.
Topics: Abscess; Endometriosis; Female; Hepatitis; Humans; Liver; Magnetic Resonance Imaging; Pelvic Inflammatory Disease; Peritoneal Diseases; Peritoneum; Peritonitis; Tomography, X-Ray Computed
PubMed: 33236541
DOI: 10.3348/kjr.2019.0774 -
Frontiers in Immunology 2023CXCL8 is the most representative chemokine produced autocrine or paracrine by tumor cells, endothelial cells and lymphocytes. It can play a key role in normal tissues... (Review)
Review
CXCL8 is the most representative chemokine produced autocrine or paracrine by tumor cells, endothelial cells and lymphocytes. It can play a key role in normal tissues and tumors by activating PI3K-Akt, PLC, JAK-STAT, and other signaling pathways after combining with CXCR1/2. The incidence of peritoneal metastasis in ovarian and gastric cancer is extremely high. The structure of the peritoneum and various peritoneal-related cells supports the peritoneal metastasis of cancers, which readily produces a poor prognosis, low 5-year survival rate, and the death of patients. Studies show that CXCL8 is excessively secreted in a variety of cancers. Thus, this paper will further elaborate on the mechanism of CXCL8 and the peritoneal metastasis of ovarian and gastric cancer to provide a theoretical basis for the proposal of new methods for the prevention, diagnosis, and treatment of cancer peritoneal metastasis.
Topics: Female; Humans; Stomach Neoplasms; Peritoneum; Peritoneal Neoplasms; Endothelial Cells; Phosphatidylinositol 3-Kinases
PubMed: 37377954
DOI: 10.3389/fimmu.2023.1159061 -
Biomolecules May 2022The peritoneal membrane is the largest internal membrane of the human body, having a surface area that approximates the surface area of the skin [...].
The peritoneal membrane is the largest internal membrane of the human body, having a surface area that approximates the surface area of the skin [...].
Topics: Humans; Membranes; Peritoneal Dialysis; Peritoneum; Skin
PubMed: 35740882
DOI: 10.3390/biom12060757 -
EMBO Molecular Medicine Mar 2023Peritoneal metastases are a common form of tumor cell dissemination in gastrointestinal malignancies. Peritoneal metastatic disease (PMD) is associated with severe... (Review)
Review
Peritoneal metastases are a common form of tumor cell dissemination in gastrointestinal malignancies. Peritoneal metastatic disease (PMD) is associated with severe morbidity and resistance to currently employed therapies. Given the distinct route of dissemination compared with distant organ metastases, and the unique microenvironment of the peritoneal cavity, specific tumor cell characteristics are needed for the development of PMD. In this review, we provide an overview of the known histopathological, genomic, and transcriptomic features of PMD. We find that cancers representing the mesenchymal subtype are strongly associated with PMD in various malignancies. Furthermore, we discuss the peritoneal niche in which the metastatic cancer cells reside, including the critical role of the peritoneal immune system. Altogether, we show that PMD should be regarded as a distinct disease entity, that requires tailored treatment strategies.
Topics: Humans; Peritoneal Neoplasms; Peritoneum; Gastrointestinal Neoplasms; Molecular Biology; Tumor Microenvironment
PubMed: 36700339
DOI: 10.15252/emmm.202215914 -
Biomolecules May 2021Post-surgical adhesions are internal scar tissue and a major health and economic burden. Adhesions affect and involve the peritoneal lining of the abdominal cavity,... (Review)
Review
Post-surgical adhesions are internal scar tissue and a major health and economic burden. Adhesions affect and involve the peritoneal lining of the abdominal cavity, which consists of a continuous mesothelial covering of the cavity wall and majority of internal organs. Our understanding of the full pathophysiology of adhesion formation is limited by the fact that the mechanisms regulating normal serosal repair and regeneration of the mesothelial layer are still being elucidated. Emerging evidence suggests that mesothelial cells do not simply form a passive barrier but perform a wide range of important regulatory functions including maintaining a healthy peritoneal homeostasis as well as orchestrating events leading to normal repair or pathological outcomes following injury. Here, we summarise recent advances in our understanding of serosal repair and adhesion formation with an emphasis on molecular mechanisms and novel gene expression signatures associated with these processes. We discuss changes in mesothelial biomolecular marker expression during peritoneal development, which may help, in part, to explain findings in adults from lineage tracing studies using experimental adhesion models. Lastly, we highlight examples of where local tissue specialisation may determine a particular response of peritoneal cells to injury.
Topics: Gene Expression Regulation, Developmental; Gene Regulatory Networks; Genetic Markers; Humans; Peritoneum; Tissue Adhesions
PubMed: 34063089
DOI: 10.3390/biom11050692