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Ren, K.;  Xie, X.;  Min, T.;  Sun, T.;  Wang, H.;  Zhang, Y.;  Dang, C.;  Zhang, H. Development of the Peritoneal Metastasis. Encyclopedia. Available online: https://encyclopedia.pub/entry/39715 (accessed on 14 December 2025).
Ren K,  Xie X,  Min T,  Sun T,  Wang H,  Zhang Y, et al. Development of the Peritoneal Metastasis. Encyclopedia. Available at: https://encyclopedia.pub/entry/39715. Accessed December 14, 2025.
Ren, Kaijie, Xin Xie, Tianhao Min, Tuanhe Sun, Haonan Wang, Yong Zhang, Chengxue Dang, Hao Zhang. "Development of the Peritoneal Metastasis" Encyclopedia, https://encyclopedia.pub/entry/39715 (accessed December 14, 2025).
Ren, K.,  Xie, X.,  Min, T.,  Sun, T.,  Wang, H.,  Zhang, Y.,  Dang, C., & Zhang, H. (2023, January 04). Development of the Peritoneal Metastasis. In Encyclopedia. https://encyclopedia.pub/entry/39715
Ren, Kaijie, et al. "Development of the Peritoneal Metastasis." Encyclopedia. Web. 04 January, 2023.
Development of the Peritoneal Metastasis
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This entry is adapted from the peer-reviewed paper 10.3390/jcm12010103

Peritoneal metastasis is a malignant disease which originated from several gastrointestinal and gynecological carcinomas and has been leading to a suffering condition in patients. As people have gradually become more aware of the severity of peritoneal carcinomatosis, new molecular mechanisms for targeting and new treatments have been proposed. 

peritoneal carcinomatosis molecular mechanisms treatment

1. Peritoneal Metastasis

1.1. Adhesion to the Peritoneum

Once tumor cells detach from the primary tumor, they float in the peritoneal fluid and travel until they contact the peritoneum. Adhesion of free cancer cells to the peritoneal surface relies on several adhesion molecular mechanisms, such as several integrins, proteoglycans and the immunoglobulin superfamily.

1.1.1. Immunoglobulin Superfamily

The immunoglobulin superfamily is a group of cell adhesion molecules, including ICAM-1, VCAM-1 and L1CAM. Intercellular adhesion molecule-1 (ICAM-1) is a surface molecule expressed by mesothelial cells, cancer cells and endothelial cells [1]. It was found that it could enhance tumor cell adhesion mediated by IL-6 or TNF-α [1]. However, Hiroaki et al. indicated that ICAM-1 could reduce lymph node metastasis, which left the specific effect of ICAM-1 in peritoneal metastasis unknown [2].
Vascular cell adhesion molecule-1 (VCAM-1) is a known, highly expressed membrane protein on mesothelial cells and has been found to play a role in adhesion to the peritoneum in ovarian cancer [3]. A current study found that VCAM-1 was related to clinicopathological factors in colorectal cancer, such as lymph node metastasis and clinical stage [4], suggesting that it might play a role in multiple types of cancer.
L1 cell adhesion molecule (L1CAM), an important molecule and marker found in ovarian cancer for poor prognosis, has been found to be related to adhesion and invasion, and an antibody against L1CAM could significantly suppress this progression [5]. It is also involved in the metastatic process in gastric cancer, predicting metastasis-related clinicopathological features and unfavorable outcomes, and could be a feasible predictor of oncological outcome [6].
Studies have found that nectin-2, an adhesion molecule participating in cell proliferation, differentiation and migration of epithelial, endothelial, immune and nervous cells, is associated with tumor growth, adhesion and angiogenesis in ovarian cancer [7]. It was found to be significantly upregulated in patients who had lymph node metastasis or residual tumors >1 cm after surgery, as well as in samples of tumor tissues and lesions on the peritoneum, which suggest its role in metastasis of ovarian cancer [8].

1.1.2. Proteoglycans

CD44, a cell-surface proteoglycan, participates in behaviors such as cell interaction, adhesion and migration. It is overexpressed in gastrointestinal and gynecological cancers [9]. Specifically, several studies found that CD44 partly mediates adhesion, such as that exhibited by cancer cells attaching to peritoneal mesothelial cells [10]. CD44-mediated adhesion could also partly explain metastasis in the inflammatory microenvironment after surgery, in which several cytokines, such as TGF-β1, IL-1b and TNF-α, are generated, resulting in upregulated CD44 expression [11].

1.1.3. Integrins

Integrins are a superfamily of cell adhesion receptors consisting of 24 members, each of which is composed of α and β subunits, and recently, integrins participating in cancer metastasis have been investigated [12]. Studies have found that integrin α2β1 participates in the peritoneal metastasis. Furthermore, it is a potential target for the treatment of peritoneal metastasis [13]. Integrin α3β1 was also found to be involved in the adherence of gastric cancer cells to the peritoneum [14]. Integrin α4β1 partly mediated peritoneal metastasis of ovarian cancer; furthermore, antibodies against it could increase ovarian cancer response to carboplatin, while treating with antibodies alone showed no response [15].
Due to the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, causing increased acetylation of HIF-1α and secretion of VEGFA. Under these conditions, VEGFA derived from peritoneal mesothelial cells acts on VEGFR1 in gastric cancer cells, increasing integrin α5 and fibronectin expression, causing further adhesion to the peritoneum [16].

1.1.4. CXC Subfamily

SDF-1α is a chemokine of the CXC subfamily on mesothelial cells. Its upregulation was indicated to possibly be due to bioactive cytokines secreted from tumor cells and was found to be associated with enhanced intraperitoneal dissemination of epithelial ovarian carcinoma cells. Another possible mechanism is that CXCR2 secreted by CT-26 colon cancer cells could induce cell proliferation and migration by combining with CXCL2 on ECM components, blocking this process inhibited cell proliferation and migration [17].

1.1.5. Other Molecules

Wnt5a is a noncanonical Wnt ligand that is highly expressed in ascites in female patients with ovarian cancer and promotes ovarian tumor cell adhesion, migration and invasion. The downstream effector is the Src family kinase Fgr, which is a potential target for the treatment of ovarian cancer [18]. Other molecules are being investigated for possible treatment.
Currently, there are various molecules in research connecting adhesion to peritoneum, and several of them showed the possibilities of predicting outcomes or providing treatment opinions. Whether those mechanisms could be used in vivo, and their effect, is still in need of investigation.

1.2. Invasion into the Peritoneum

After adhesion, tumor cells need to invade the submesothelial tissue to achieve colonization; this process could be adhering to the ECM through the gap between mesothelial cells or directly induce mesothelial cell apoptosis. Carbon dioxide pneumoperitoneum temporarily enlarges intercellular clefts and exposes the ECM, allowing tumor cells to access the ECM more easily by using RGD peptides or pseudo-RGD peptides [19]. Tumor cells could also directly influence the function of mesothelial cells. Heath et al. found that SW480 colorectal cancer cells could induce FAS-dependent apoptosis of cultured human mesothelial cells and that tumor–mesothelial adhesion was essential for inducing apoptosis.
Several studies have shown that matrix metalloproteinases (MMPs) contribute to the invasion of the submesothelial tissue by causing degradation of the ECM and contraction of mesothelial cells. MMPs are a family of zinc-dependent endopeptidases that are involved in the degradation of various proteins in the extracellular matrix (ECM). Their functions in cancer invasion and metastasis have been found gradually. MMP-7 is likely to be associated with adhesion, as the downregulation of MMP-7 could suppress invasion without influencing proliferation; it also takes part in serosal involvement, lymph node metastasis, poor differentiation of cancer and peritoneal dissemination, indicating its role in peritoneal adhesion [20]. Another matrix metalloproteinase is MMP-9. In vitro studies have shown that peritoneal mesothelial cells can also secrete MMP-9 under TNF-α stimulation in gastric cancer cells, which enhances cancer cell invasion [21]. MMP2/9 were found strongly upregulated in colon tumor tissues, and inhibition of them could reduce colonization [22].

2. Diagnosis and Evaluation of Peritoneal Metastasis

The diagnosis of peritoneal carcinomatosis relies on imaging, biopsy and laparoscopy. CT and PET/CT are the most used methods for the detection of peritoneal metastasis; an enhanced CT scan could provide valuable information for metastasis detection [23], especially for pseudomyxoma peritonei [24]. PET/CT with radioisotopes is more sensitive for diagnosis than CT, according to Koh et al. [25]; however, other research found CT to be more sensitive than PET/CT for diagnosis [26]. PET is traditionally more sensitive to tumors with hypermetabolic uptake, but not minor nodules [25][27]. Diffusion-weighted (DW) MRI was another method and seemed to be the same as CT in sensitivity or PET/CT in diagnosis [28][29]. In addition, PET/CT appeared favorable in sensitivity as well, but showed weak ability in excluding diagnosis of peritoneal metastasis [30][31]. Imaging methods can assist in assessing peritoneal metastasis, thus evaluating if cytoreduction is possible. Compared with imaging, the most precise method of diagnosis is peritoneal visualization and biopsy, for example, exploratory laparotomy, but this approach is invasive [32]. It is worth noting that, recently, a fluorescent probe called gGlu-HMRG had been used to detect tiny tumors on the peritoneal wall, showing potential in both diagnosis and assistance for fluorescence-guided surgery for peritoneal carcinomatosis [33]. Currently, despite the limitations of CT, it is a still powerful and cost-effective tool for general metastasis detection, making it the first choice for detection and diagnosis; PET/CT and MRI could be used in an alternative way and in specific situations.
A way of evaluating peritoneal metastasis is using the peritoneal cancer index (PCI). PCI includes the surgical peritoneal cancer index (sPCI) and pathologic peritoneal index (pPCI), the former of which requires evaluating peritoneal metastasis during surgery. Surgeons record the number and size of lesions in each of the 13 peritoneal regions and add them to obtain the sPCI. The pPCI is scored through the pathologic evaluation of specimens. sPCI and pPCI do not always seem consistent, for the former is mostly subjective, though sPCI could provide valuable information for the evaluation of patients [34]. Though pPCI is more objective, specimens would shrink during the process, causing misjudgment of tumor size. Furthermore, there were no standard procedures for the evaluation of specimens from CRS, thus, further research needs to be conducted [35]. CT-PCI used a CT scan for the evaluation of the disease burden and prognosis, helping for these aspects, regardless of its accuracy [27][36].
It is also interesting to evaluate whether there were differences between primary tumors and metastasis tumors in molecular and gene expression to further understand the mechanisms of metastasis and to provide targeted treatment. Several studies found high consistency in colorectal cancer in both dMMR, MSI status and biomarkers [37][38]; however, there were other studies that found different expression in colorectal cancer between primary tumor and metastases, a significant enrichment for CMS4 in peritoneal metastasis, providing a possible treatment combined with CRS-HIPEC to reduce metastasis tumors [39]. Furthermore, different expressions or mutations were detected in gastric cancer based on a multi-omic profiling, suggesting a molecular-targeting therapy separate from therapy on primary tumors.
The differences of biomarkers between colorectal cancer and its metastases have been compared [40][41], including KRAS/BRAF mutation and MSI status, indicating the importance of testing mutations in peritoneal metastasis and treating methods. However, there is still in lack of research and data in the area, which suggests a further evaluation of personalized treatment.

3. Treatment to Peritoneal Metastasis

In surgery for primary tumors, traditional ways to reduce the incidence of peritoneal metastasis are to follow a no-touch isolation technique (NTIT)—complete removal of adjacent invaded structures and surgical margins deep in the healthy tissue—and other standard surgery procedures, which reduce the feasibility of surgery-induced local metastasis and blood metastasis [42]. However, recent clinical trials questioned the superiority of the NTIT [43], indicating that further treatments are needed.
Intraperitoneal chemotherapy has been widely applied, compared to systemic chemotherapy for peritoneal carcinomatosis, because not all reagents of systemically applied chemotherapy could be fully delivered to the peritoneum, possibly due to the peritoneum-plasma barrier. This barrier leads to peritoneal clearance being much slower than systemic clearance; thus, a high intraperitoneal chemotherapy dose would result in moderate systemic drug exposure [44].
HIPEC, known as hyperthermic intraperitoneal chemotherapy, uses specific chemical reagents and a high temperature to kill tumor cells. It has mainly been evaluated in peritoneal carcinomatosis in colorectal, mucinous appendicular adenocarcinoma and ovarian cancer [45][46][47][48][49][50]. The main advantage of HIPEC is the maintenance of a high regional reagent concentration, and blood drainage of the peritoneal surface occurs via the portal vein to the liver. Increasing the concentration in the liver would suppress liver metastasis as well. Another advantage is that 41–43 °C hyperthermia could directly kill tumor cells by inhibiting RNA synthesis and mitotic arrest and increasing the number of lysosomes and the activity of lysosomal enzymes. Heat also increases the cytotoxicity of certain chemotherapeutic drugs and enhances tissue penetration [51]. HIPEC is usually administered in the operating room immediately after CRS, due to limited drug penetration in tumor tissues, and is mainly used to kill microscopic residual disease after CRS.
However, due to the direct administration of drugs into the peritoneum, choices of these drugs must meet certain criteria. Typically, these reagents should be effective against malignant cells and low local toxicity after administration. Additionally, these reagents should be cycle-nonspecific and induce heat-synergized effects [51]. Specific reagent effects, toxicity to malignant cells and penetration into tumor tissues during systemic chemotherapy should be considered to determine which method is more effective. Reagents that require transformation into an active form in the liver should be excluded. In addition, the most important feature is that reagents should be slowly absorbed from the peritoneal cavity and rapidly cleared via hepatic and/or renal mechanisms so that a high concentration of drug can be maintained with low systemic toxicity [52].
Several studies have compared factors influencing the outcomes of CRS-HIPEC. Though most studies used different strategies, the results suggested that a patient’s survival was prolonged after a complete procedure. Factors involved in HIPEC include choices of drugs, applied dose, duration, carrier solution, perfusate volume, perfusate concentration and use of an open vs. closed technique [52]. Interestingly, repeated CRS-HIPECs seemed to be beneficial for patients occurring metastasis limited to peritoneum, suggesting that it might be suitable for specific patients to prolong survival [53]. However, HIPEC had risks of causing changes to genetic patterns between tumors and normal tissues and an upregulation of heat shock-related genes, to be specific, which would be an adverse effect, and an idea of combining other treatments [54].
There are new methods, such as electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC), which use electrostatic precipitation of aerosols to achieve stronger penetration and more even distribution [55]. Studies have tested safety and tolerance in treated patients, but efficiency was debatable [56][57]. Another new method, hyperthermic pressurized intraperitoneal aerosol chemotherapy (hPIPAC), which involves the application of cisplatin at temperatures of 38.8–40.2 °C [58], has been proposed and tested recently. Both require further experiments to evaluate feasibility and long-term therapeutic effect.
High-intensity ultrasound (HIUS) has been studied to treat several solid tumors, and the purpose of HIUS was to further enhance tissue penetration, which has been reported [59]. The damage HIUS could cause has also been assessed, and it could yield measurable microscopic changes on the peritoneal surface with minimal damage [60]; however, as a new theory, specifics regarding its usage, safety and combination with other methods, such as CRS plus HIPEC, PIPAC or new biocompatible materials, should be further assessed.
Neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) is a new method aiming to increase possibilities to access CRS, especially for those whose tumor features are not suitable for CRS. A meta-analysis was performed on 8 retrospective studies, including 373 patients with peritoneal metastasis from gastric cancer, 109 of whom continued NIPS treatment because of macroscopic peritoneal metastasis and 265 of whom received surgery for no macroscopic peritoneal metastasis. NIPS combined with surgery significantly improved survival compared to those without surgery, and NIPS could increase the possibility of achieving R0 resection [61]. Other studies supported the idea that NIPS could be used for advanced gastric cancer with peritoneal metastasis [62]. Due to a lack of further clinical data, more clinical trials and research should be conducted to confirm and evaluate this hypothesis.
Drugs targeting adhesion molecules and immunotherapies have shown potential in preventing peritoneal metastasis. Zang et al. found that LPPR4 (which plays a role in promoting peritoneal metastasis of gastric cancer through Sp1/integrin α/FAK signaling) could be a new therapeutic target [63]. The binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to antiapoptotic signaling through Bcl-2 and Survivin upregulation; it also promotes EMT through the Rho-ROCK pathway and leads to alterations in cell adhesion molecules. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist used in clinical trials for gastrointestinal tumors [64] and shows potential prospect. Methods activating immune effects of anti–tumors were investigated due to the high expression of PD-L1 during the process of peritoneal metastasis [65]. CMP-001, a virus-like particle composed of the Qβ bacteriophage capsid protein, encapsulating a CpG-A oligodeoxynucleotide, could activate lasmacytoid dendritic cells and interferon alpha release [66], which might contribute to an anti-tumor response by the development of T-cells [67]. Similarly, oncolytic virotherapy was also classified as another type of immunotherapy; this therapy used viruses as oncolytic vector platforms for the delivery of different treatment agents, such as therapeutic genes, prodrug convertases, toxins, sodium iodide symporter for radiotherapy and immunomodulators [68][69]. JX-594 (pexastimogene devacirepvec, Pexa-vec) is an oncolytic vaccinia virus armed with GM-CSF; a murine version of it shows potential as an anti-tumor by activating dendritic cells and CD8 T cells to enhance their infiltration into peritoneal tumor nodules. Furthermore, it could combine with immune checkpoint inhibitors to induce enhanced immunity to kill metastases [70].
Localized chemotherapy could decrease the toxicity of chemical drugs systemically and maintain a higher concentration in specific areas. In addition to HIPEC and PIPAC, new delivery systems are being studied. Biocompatible carrier systems, such as hydrogels, cells and peptides, have been used for localized drug delivery for the treatment of peritoneal metastasis.
Another delivery system utilizes cells as carriers. Ling et al. used engineered doxorubicin-loaded M1 macrophages (M1-Dox), which overexpress CCR2 and CCR4, to target cancer cells; M1-Dox transferred drug cargoes into tumor cells via a tunneling nanotube pathway. The results showed that delivering drugs (Dox) from cell to cell was more efficient than lysosomal delivery in terms of effective concentration and drug loading. Furthermore, these cells were not only effective in treating primary tumors, but also had a great advantage in treating metastasis [71]. Functional amyloids produced in bacteria as nanoscale inclusion bodies are a new pathway for treatment. Céspedes et al. used Pseudomonas exotoxin (PE24)-formed bacterial inclusion bodies functionalized with CXCR4 and found that colorectal cancer mouse models treated with these proteins showed significant arrest of tumor growth without toxicity [72]. Albumin, with multiple cellular receptor and ligand binding sites, which are able to bind and transport numerous endogenous and exogenous compounds, could also act as a carrier for chemotherapy drugs targeting peritoneal metastasis, providing a more biocompatible approach for drug delivery [73].

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Kaijie Ren ,
Xin Xie
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Tianhao Min
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Tuanhe Sun
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Haonan Wang
, Yong Zhang , Chengxue Dang , Hao Zhang
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Update Date: 05 Jan 2023
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