• Basal cell adhesion molecule (BCAM)
• Cancer cell migration
• Mesothelial-to-mesenchymal transition (MMT)
• Ovarian cancer metastasis
• Tumor angiogenesis

• Humans
• Animals
• Paracrine Communication
• Epithelial-Mesenchymal Transition
• Female
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Mice
• Cell Adhesion Molecules/metabolism
• Cell Adhesion Molecules/genetics
• Cell Line, Tumor
• Ovarian Neoplasms/pathology
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/blood supply
• Cell Movement
• Cytokines/metabolism
• Angiogenesis

• Philipps-Universität Marburg (1009)

• Colorectal cancer
• Cytoreductive surgery
• Heated intraperitoneal chemotherapy
• Peritoneal metastasis

• Humans
• Colorectal Neoplasms/pathology
• Peritoneal Neoplasms/secondary
• Peritoneal Neoplasms/surgery
• Peritoneal Neoplasms/therapy
• Peritoneal Neoplasms/mortality
• Peritoneal Neoplasms/drug therapy
• Cytoreduction Surgical Procedures/methods
• Hyperthermic Intraperitoneal Chemotherapy

• metastasis
• pathophysiology
• peritoneal

• Humans
• Peritoneal Neoplasms/secondary
• Peritoneal Neoplasms/physiopathology
• Peritoneum/pathology
• Peritoneum/physiopathology

• Th17 cells
• mesothelial cells
• metastasis
• ovarian carcinoma

• Humans
• Female
• Th17 Cells
• Interleukin-17/metabolism
• Cytokines/metabolism
• Ovarian Neoplasms/metabolism
• Inflammation/metabolism
• Tumor Microenvironment

• GRK2573 Deutsche Forschungsgemeinschaft
• SFB1292-TP22 Deutsche Forschungsgemeinschaft
• SFB1292-TPQ1 Deutsche Forschungsgemeinschaft
• GA1818/2-3 Deutsche Forschungsgemeinschaft
• Deutsche Forschungsgemeinschaft

• Cancer
• Immunology
• Microenvironment

• colorectal cancer (CRC)
• cytoreductive surgery (CRS)
• intraperitoneal chemotherapy (IPC)
• intraperitoneal free cancer cells (IFCCs)
• peritoneal metastasis (PM)

• No. 82002479 National Natural Science Foundation of China
• No. BK20200179 Natural Science Foundation of Jiangsu Province
• No. CZQM2020006 Young Talent Development Plan of Changzhou Health Commission
• 202162 Young Scientific and Technological Talent Support Project of Changzhou
• No. 2022260: KY20221354，KY20221355 Changzhou "14th Five-Year Plan" High-level Health Personnel Training Project

• combined treatment
• cytoreductive surgery
• intraperitoneal chemotherapy
• peritoneal metastatic cancer
• systemic chemotherapy
• therapeutic nanoagents

• Humans
• Peritoneal Neoplasms/therapy
• Peritoneum
• Quality of Life
• Ascites
• Combined Modality Therapy

• biomaterial
• diagnosis
• peritoneal surface malignancy
• treatment

• Humans
• Pleural Effusion, Malignant/diagnostic imaging
• Pleural Effusion, Malignant/etiology
• Pleural Effusion, Malignant/therapy
• Quality of Life
• Catheters, Indwelling/adverse effects
• Pleural Cavity
• Melanoma/complications
• Drainage/adverse effects
• Drainage/methods
• Pleurodesis/methods

• ADAM10
• BCAM
• ovarian cancer
• spheroids

• Animals
• Female
• Humans
• Mice
• Cell Adhesion/physiology
• Cell Adhesion Molecules/metabolism
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Spheroids, Cellular

• German Research Foundation

• molecular mechanisms
• peritoneal carcinomatosis
• treatment

• mesothelial–mesenchymal transition
• peritoneal mesothelial cells
• peritoneal metastatic cancer

• 20JR10RA372 Natural Science Foundation of Gansu Province
• GSWSKY-2019-03 Health Industry Research Project of Gansu Province
• 19SYPYB-10 National scientific research project support program of Gansu Provincial Hospital
• 2020GSZDSYS02 Open fund project of Gansu Key Laboratory of Molecular Diagnosis and Precision Therapy of Surgical Oncology
• NLDTG2020020 Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences

In the USA, more than 50% of patients with ovarian cancer die within 5 years of diagnosis, highlighting the need for therapeutic innovations. Mesothelin (MSLN) is a candidate immunotherapy target; it is overexpressed by ovarian tumors and contributes to malignant/invasive phenotypes, making tumor antigen loss disadvantageous. We previously showed that MSLN-specific T cell receptor (TCR)-engineered T cells preferentially accumulate within established tumors, delay tumor growth, and significantly prolong survival in the ID8_VEGF mouse model that replicates many aspects of human disease. However, T cell persistence and antitumor activity were not sustained. We therefore focused on Fas/FasL signaling that can induce activation-induced cell death, an apoptotic mechanism that regulates T cell expansion. Upregulation of FasL by tumor cells and tumor vasculature has been detected in the tumor microenvironment (TME) of human and murine ovarian cancers, can induce apoptosis in infiltrating, Fas (CD95) receptor-expressing lymphocytes, and can protect ovarian cancers from tumor-infiltrating lymphocytes.

To overcome potential FasL-mediated immune evasion and enhance T cell responses, we generated an immunomodulatory fusion protein (IFP) containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain, rather than the natural death domain. Murine T cells were engineered to express an MSLN-specific TCR (TCR₁₀₄₅), alone or with the IFP, transferred into ID8_VEGF tumor-bearing mice and evaluated for persistence, proliferation, cytokine production and efficacy. Human T cells were similarly engineered to express an MSLN-specific TCR (TCR₅₃₀) alone or with a truncated Fas receptor or a Fas-4-1BB IFP and evaluated for cytokine production and tumor lysis.

Relative to murine T cells expressing only TCR₁₀₄₅, T cells expressing both TCR₁₀₄₅ and a Fas-4-1BB IFP preferentially persisted in the TME of tumor-bearing mice, with improved T cell proliferation and survival. Moreover, TCR₁₀₄₅/IFP⁺ T cells significantly prolonged survival in tumor-bearing mice, compared with TCR₁₀₄₅-only T cells. Human T cells expressing TCR₅₃₀ and a Fas-4-1BB IFP exhibit enhanced functional activity and viability compared with cells with only TCR₅₃₀.

As many ovarian tumors overexpress FasL, an IFP that converts the Fas-mediated death signal into pro-survival and proliferative signals may be used to enhance engineered adoptive T cell therapy for patients.

• cell engineering
• costimulatory and inhibitory T-Cell receptors
• genital neoplasms, female
• immunotherapy, adoptive
• tumor microenvironment

Surgical and locoregional treatments of peritoneal metastasis, e.g., from colorectal cancer, has gained increasing acceptance after the publication of excellent patient outcomes from many groups around the world. Apart from systemic chemotherapy and surgical removal of the tumor, locoregional therapies such as HIPEC or PIPAC may improve tumor control. Understanding the molecular characteristics of peritoneal metastasis is crucial to evolve future therapeutic strategies for peritoneal metastasis. This includes the genetic background of PM, which is often different from other sites of metastasis, and promotes peritoneal dissemination and the growth of tumor cells. Growing knowledge and insight into the physiology of the peritoneal tumor microenvironment and the specific role of the immune system in this compartment may provide a critical step to move locoregional therapy to the next level. This review summarizes the current knowledge and highlights the molecular characteristics of peritoneal metastasis.

Peritoneal metastasis (PM) originating from gastrointestinal cancer was considered a terminal disease until recently. The advent of better systemic treatment, a better understanding of prognostic factors, and finally, the advent of novel loco-regional therapies, has opened the door for the multimodal treatment of PM. These strategies, including radical surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) showed surprisingly good results, leading to the prolonged survival of patients with peritoneal metastasis. This has triggered a significant body of research, leading to the molecular characterization of PM, which may further help in the development of novel treatments. This review summarizes current evidence on peritoneal metastasis and explores potential novel mechanisms and therapeutic approaches to treat patients with peritoneal metastasis.

• colorectal cancer (CRC)
• cytoreductive surgery
• hyperthermic intraperitoneal chemotherapy
• peritoneal metastasis
• tumor biology

• CD44
• Hyaluronan
• ICAM-1
• Peritoneum
• RHAMM

• HSP70
• WNT4
• adipocyte
• carcinoma-associated fibroblast
• mesothelial cell
• metastasis
• omentum
• ovarian carcinoma
• signaling network
• tumour microenvironment

• Cell Movement/genetics
• Cell Movement/physiology
• Female
• Gene Regulatory Networks/genetics
• Gene Regulatory Networks/physiology
• Humans
• Neoplasm Metastasis/immunology
• Neoplasm Metastasis/physiopathology
• Ovarian Neoplasms/immunology
• Ovarian Neoplasms/physiopathology
• Signal Transduction/genetics
• Signal Transduction/physiology

• 70113255 Deutsche Krebshilfe (German Cancer Aid)

• EMT
• Metastasis
• Ovarian cancer
• TGFβ
• Tumor microenvironment

• Carcinoma, Ovarian Epithelial/drug therapy
• Carcinoma, Ovarian Epithelial/pathology
• Disease Progression
• Epithelial-Mesenchymal Transition/drug effects
• Female
• Humans
• Neoplasm Metastasis
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/pathology
• Signal Transduction/physiology
• Smad Proteins/physiology
• Transforming Growth Factor beta/antagonists & inhibitors
• Transforming Growth Factor beta/physiology

• 29802 Cancer Research UK
• R01 CA219495 NCI NIH HHS
• R01 CA230628 NCI NIH HHS
• R01 GM128055 NIGMS NIH HHS
• National Cancer Institute
• National Institute of General Medical Sciences

Ovarian cancer cells mainly metastasise within the peritoneal cavity, the lethal consequence of tumour progression in this cancer type. Classically, changes in tumour cells, such as epithelial to mesenchymal transition, involve the down-regulatinon of E-cadherin, activation of extracellular proteases and integrin-mediated adhesion. However, our current understanding of ovarian tumour progression suggests the implication of both intrinsic and extrinsic factors. It has been proposed that ovarian cancer metastases are a consequence of the crosstalk between cancer cells and the tumour microenvironment by soluble factors and extracellular vesicles. Characterisation of the alterations in both the tumour cells and the surrounding microenvironment has emerged as a new research field to understand ovarian cancer metastasis. In this mini review, we will summarise the most recent findings, focusing our attention on the role of secreted factors and extracellular vesicles in ovarian cancer metastasis.

•

During ovarian cancer metastasis, tumour cells metastasise in the mesothelium as primarily ‘soil’ for ovarian cancer ‘seeds’.

• Cancer
• Exosomes
• Extracellular vesicles
• Metastasis

A hallmark of ovarian high‐grade serous carcinoma (HGSC) is its early and massive peritoneal dissemination via the peritoneal fluid. It is generally believed that tumor cells must breach the mesothelium of peritoneal organs to adhere to the underlying extracellular matrix (ECM) and initiate metastatic growth. However, the molecular mechanisms underlying these processes are only partially understood. Here, we have analyzed 52 matched samples of spheroids and solid tumor masses (suspected primary lesions and metastases) from 10 patients by targeted sequencing of 21 loci previously proposed as targets of HGSC driver mutations. This analysis revealed very similar patterns of genetic alterations in all samples. One exception was FAT3 with a strong enrichment of mutations in metastases compared with presumed primary lesions in two cases. FAT3 is a putative tumor suppressor gene that codes for an atypical cadherin, pointing a potential role in peritoneal dissemination in a subgroup of HGSC patients. By contrast, transcriptome data revealed clear and consistent differences between tumor cell spheroids from ascites and metastatic lesions, which were mirrored by the in vitro adherence of ascites‐derived spheroids. The adhesion‐induced transcriptional alterations in metastases and adherent cells resembled epithelial–mesenchymal transition, but surprisingly also included the upregulation of a specific subset of mesothelial genes, such as calretinin (CALB2) and podoplanin (PDPN). Consistent with this finding, calretinin staining was also observed in subsets of tumor cells in HGSC metastases, particularly at the invasive tumor edges. Intriguingly, a high expression of either CALB2 or PDPN was strongly associated with a poor clinical outcome. siRNA‐mediated CALB2 silencing triggered the detachment of adherent HGSC cells in vitro and inhibited the adhesion of detached HGSC cells to collagen type I. Our data suggest that the acquisition of a mesenchymal–mesothelial phenotype contributes to cancer cell adhesion to the ECM of peritoneal organs and HGSC progression.

• adhesion
• calretinin
• driver mutations
• mesothelial cells
• metastasis
• ovarian cancer
• podoplanin
• transcriptomics

• cytopathology
• effusion cytology
• pleural effusion

• cytoreductive surgery
• hyperthermic intraperitoneal chemotherapy
• peritoneal disease

• colorectal cancer
• peritoneal metastasis
• tumor microenvironment

• antitumor immunity
• dendritic cells
• immune inhibition
• immunotherapy
• tumor microenvironment
• tumor-associated macrophages
• tumor-infiltrating lymphocytes

• antitumor immunity
• dendritic cells
• immune inhibition
• immunotherapy
• tumor microenvironment
• tumor-associated macrophages
• tumor-infiltrating lymphocytes

• antitumor immunity
• dendritic cells
• immune inhibition
• immunotherapy
• tumor microenvironment
• tumor-associated macrophages
• tumor-infiltrating lymphocytes

Peritoneal metastasis is one of the major patterns of unresectability in colorectal cancer (CRC) and a cause of death in advanced CRC. Identification of distinct gene expressions between primary CRC and peritoneal seeding metastasis is to predict the metastatic potential of primary human CRC. Three pairs of primary CRC (SNU-2335A, SNU-2404A, and SNU-2414A) and corresponding peritoneal seeding (SNU-2335D, SNU-2404B, and SNU-2414B) cell lines were established to determine the different gene expressions and resulting aberrated signaling pathways in peritoneal metastasis tumor using whole exome sequencing and microarray. Whole exome sequencing detected that mutation in CYP2A7 was exclusively shared in peritoneal seeding cell lines. Microarray identified that there were five upregulated genes (CNN3, SORBS1, BST2, EPSTI1, and KLHL5) and two downregulated genes (TRY6 and STYL5) in the peritoneal metastatic cell lines. CNN3 expression was highly augmented in both mRNA and protein levels in peritoneal metastasis cells. Knockdown of Calponin 3 resulted in augmented level of E-cadherin in peritoneal metastasis cells, and migration and invasiveness decreased accordingly. We suggest that CNN3 takes part in cell projection and movement, and the detection and distribution of CNN3 may render prognostic information for predicting peritoneal seeding metastasis from primary colorectal cancer.

• Cancer metastases
• Peritoneal cavity
• Reactive stroma
• Seed and soil theory

• Animals
• Carcinogenesis/pathology
• Humans
• Neoplasms/pathology
• Peritoneal Neoplasms/secondary
• Peritoneum/pathology
• Peritoneum/physiology
• Tumor Microenvironment/physiology

• 2014/15/B/NZ3/00421 Narodowe Centrum Nauki

• exosome
• gastric cancer
• mesothelial barrier destruction
• peritoneal mesothelial cell
• peritoneal metastasis

• colorectal neoplasm
• experimental model
• mesothelial cell
• peritoneal neoplasm
• peritoneum

The reciprocal interplay of cancer cells and host cells is an indispensable prerequisite for tumor growth and progression. Cells of both the innate and adaptive immune system, in particular tumor-associated macrophages (TAMs) and T cells, as well as cancer-associated fibroblasts enter into a malicious liaison with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Ovarian cancer, the most lethal of all gynecological malignancies, is characterized by a unique TME that enables specific and efficient metastatic routes, impairs immune surveillance, and mediates therapy resistance. A characteristic feature of the ovarian cancer TME is the role of resident host cells, in particular activated mesothelial cells, which line the peritoneal cavity in huge numbers, as well as adipocytes of the omentum, the preferred site of metastatic lesions. Another crucial factor is the peritoneal fluid, which enables the transcoelomic spread of tumor cells to other pelvic and peritoneal organs, and occurs at more advanced stages as a malignancy-associated effusion. This ascites is rich in tumor-promoting soluble factors, extracellular vesicles and detached cancer cells as well as large numbers of T cells, TAMs, and other host cells, which cooperate with resident host cells to support tumor progression and immune evasion. In this review, we summarize and discuss our current knowledge of the cellular and molecular interactions that govern this interplay with a focus on signaling networks formed by cytokines, lipids, and extracellular vesicles; the pathophysiologial roles of TAMs and T cells; the mechanism of transcoelomic metastasis; and the cell type selective processing of signals from the TME.

• NFκB
• STAT
• T cell
• T cell checkpoints
• adhesion
• ascites
• extracellular vesicles
• invasion
• mesothelial cell
• metastasis
• tumor microenvironment
• tumor-associated macrophage

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread.

• Peritoneal carcinomatosis
• Pathophysiology
• Peritoneal metastatic cascade
• Cytoreductive surgery
• Peritoneum
• Hyperthermic intraperitoneal peroperative chemotherapy

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma/physiopathology
• Carcinoma/surgery
• Cell Proliferation
• Chemotherapy, Cancer, Regional Perfusion
• Colorectal Neoplasms/physiopathology
• Colorectal Neoplasms/surgery
• Combined Modality Therapy
• Cytoreduction Surgical Procedures
• Humans
• Hyperthermia, Induced
• Neovascularization, Pathologic
• Peritoneal Neoplasms/physiopathology
• Peritoneal Neoplasms/surgery
• Peritoneum/physiopathology
• Peritoneum/surgery
• Quality of Life

• carcinoma-associated fibroblasts
• mesothelial cells
• mesothelial-to-mesenchymal transition
• peritoneal metastasis
• therapeutic strategies

• apoptosis
• breast carcinoma
• emodin
• growth inhibition

Peritoneal carcinomatosis (PC), the dissemination of cancer cells throughout the lining of the abdominal cavity, is the second most common presentation of colon cancer distant metastasis. Despite remarkable advances in cytotoxic chemotherapy and targeted therapy for colon cancer over the last 15 years, it has been repeatedly shown that these therapies remain ineffective for colon cancer PC. Recently, there has been a rapid accumulation of reports that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) prolongs the life of colon cancer PC patients. Here, we will review the clinical presentation, the mechanisms of disease progression, and current treatment options for colon cancer PC, with a focus on the benefits and limitations of CRS-HIPEC.

• Cancer
• Colorectal
• Carcinomatosis
• Peritoneal
• Hyperthermic intraperitoneal chemotherapy
• Intraperitoneal chemotherapy
• Cytoreductive surgery
• Mechanism

• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/adverse effects
• Carcinoma/mortality
• Carcinoma/secondary
• Carcinoma/therapy
• Chemotherapy, Adjuvant
• Colonic Neoplasms/mortality
• Colonic Neoplasms/pathology
• Cytoreduction Surgical Procedures/adverse effects
• Cytoreduction Surgical Procedures/mortality
• Drug Administration Schedule
• Humans
• Hypothermia, Induced/adverse effects
• Hypothermia, Induced/mortality
• Infusions, Parenteral
• Peritoneal Neoplasms/mortality
• Peritoneal Neoplasms/secondary
• Peritoneal Neoplasms/therapy
• Treatment Outcome

• Animals
• Cell Adhesion
• Cell Line, Tumor
• Coculture Techniques
• Epithelial Cells/cytology
• Extracellular Matrix/metabolism
• Female
• Fibronectins/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Integrins/metabolism
• Mice
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• RNA, Small Interfering/metabolism
• Signal Transduction
• Transforming Growth Factor beta1/metabolism

• K12 HD000849 NICHD NIH HHS
• R01 CA111882 NCI NIH HHS

• Curcumin
• apoptosis
• breast carcinoma
• nude mice

• Animals
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Blotting, Western
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Curcumin/pharmacology
• Female
• Flow Cytometry
• Humans
• In Vitro Techniques
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microscopy, Electron, Transmission
• Xenograft Model Antitumor Assays

• force
• integrins
• mesothelium
• myosin
• ovarian cancer

• Cell Adhesion/physiology
• Epithelium/metabolism
• Epithelium/pathology
• Female
• Fibronectins/metabolism
• Humans
• Integrin alpha5beta1/metabolism
• Myosin Type II/metabolism
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Peritoneal Cavity/pathology
• Peritoneum/metabolism
• Peritoneum/pathology
• Spheroids, Cellular/metabolism
• Spheroids, Cellular/pathology
• Talin/metabolism
• Tumor Cells, Cultured

• 5695837 PHS HHS
• R01 CA105134-09 NCI NIH HHS
• R01 GM071868-06 NIGMS NIH HHS
• R01 CA105134 NCI NIH HHS
• R01 GM071868 NIGMS NIH HHS

In this study, we examined effects of soluble factors released by gastric cancer cells on peritoneal mesothelial cells in vitro and in vivo.

HMrSV5, a human peritoneal mesothelial cell line, was incubated with supernatants from gastric cancer cells. Morphological changes of HMrSV5 cells were observed. Apoptosis of HMrSV5 cells was observed under a transmission electron microscope and quantitatively determined by MTT assay and flow cytometry. Expressions of apoptosis-related proteins (caspase-3, caspase-8, Bax, bcl-2) were immunochemically evaluated.

Conspicuous morphological changes indicating apoptosis were observed in HMrSV5 cells 24 h after treatment with the supernatants of gastric cancer cells. In vivo, peritoneal tissues treated with gastric cancer cell supernatant were substantially thickened and contained extensive fibrosis.

These findings demonstrate that supernatants of gastric cancer cells can induce apoptosis and fibrosis in HMrSV5 human peritoneal mesothelial cells through supernatants in the early peritoneal metastasis, in a time-dependent manner, and indicate that soluble factors in the peritoneal cavity affect the morphology and function of mesothelial cells so that the resulting environment can become favorable to peritoneal metastases.