Anoikis resistant gastric cancer cells promote angiogenesis and peritoneal metastasis through C/EBPβ-mediated PDGFB autocrine and paracrine signaling

Du, Shangce; Yang, Zhi; Lu, Xiaofeng; Yousuf, Suhail; Zhao, Min; Li, Wenxi; Miao, Ji; Wang, Xingzhou; Heng, Yu; Zhu, Xinya; Chen, Hong; Shi, Linseng; Xu, En; Xia, Xuefeng; Guan, Wenxian

doi:10.1038/s41388-021-01988-y

Cited by 59 publications

(38 citation statements)

References 59 publications

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“…[13][14][15][16] Resistance to anoikis is a hallmark of PM because intraperitoneal free cancer cells that have migrated from the primary tumor survive in an anchorage-independent manner. 17 Therefore, GC cells require sufficient ATP generation, increased biosynthesis of biomolecules, and maintenance of an appropriate redox status despite the low oxygen (hypoxia) and nutrient levels within the peritoneal cavity. Little is known about the expression of CD36 and its mechanistic role in PM.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake

et al. 2022

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Background The lipid scavenger receptor cluster of differentiation 36 (CD36) has been shown to have a pro-metastatic function in several cancers. Adipose tissue, a favorable site for peritoneal metastasis (PM) from gastric cancer (GC), promotes this process by providing free fatty acids (FFAs); however, the role of CD36 in PM progression from GC remains to be elucidated. Materials and Methods We evaluated CD36 expression in the GC cells under various conditions. CD36 overexpressing (CD36OE) MKN45 cells were prepared and their migration and invasive properties were assessed. A PM mouse model was used to investigate the biological effects of palmitic acid (PA) and CD36. Furthermore, we examined the clinical role of CD36 expression in 82 human PM samples by immunohistochemical staining. Results Hypoxia markedly increased CD36 expression in GC cells. In normoxia, only CD36OE MKN45 cells treated with PA showed an increase in migration and invasion abilities. An increased expression of active Rac1 and Cdc42 was observed, which decreased following etomoxir treatment. Conversely, hypoxia increased those capacities of both vector and CD36OE MKN45 cells. In a mouse model transplanted with CD36OE MKN45 cells, more peritoneal tumors were observed in the high-fat diet group than those in the normal diet group. In clinical samples, 80% of PM lesions expressed CD36, consistent with hypoxic regions, indicating a significant association with prognosis. Conclusion Our findings indicate that a hypoxia in the peritoneal cavity induces CD36 expression in GC cells, which contributes to PM through the uptake of FFAs.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake

et al. 2022

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“…These results indicate that PFCCs attach to the peritoneal surface and invade the subperitoneal tissue by a mechanism involving the concerted expression of motility factors [50][51][52][53][54][55][56] matrix digesting enzymes [57][58][59][60][61][62][63][64][65][66][67][68][69], and adhesion molecules [44][45][46]70,71]. As PFCCs grow in the subperitoneal tissue, a new vascular network forms in response to the secretion of angiogenesis factors from cancer cells and surrounding interstitial cells (Figure 17) [72][73][74]. As shown in Figure 17C,D, CD34-positive interstitial fibroblasts are found in the stromal tissue, and newly formed blood vessels are detected in the stromal tissues of established trans-mesothelial metastasis.…”

Section: Mechanisms Of Trans-mesothelial Metastasismentioning

confidence: 99%

The Development of Peritoneal Metastasis from Gastric Cancer and Rationale of Treatment According to the Mechanism

Yonemura

Ishibashi

Mizumoto

et al. 2022

JCM

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In the present article, we describe the normal structure of the peritoneum and review the mechanisms of peritoneal metastasis (PM) from gastric cancer (GC). The structure of the peritoneum was studied by a double-enzyme staining method using alkaline-phosphatase and 5′-nucreotidase, scanning electron microscopy, and immunohistological methods. The fundamental structure consists of three layers, mesothelial cells and a basement membrane (layer 1), macula cribriformis (MC) (layer 2), and submesothelial connective tissue containing blood vessels and initial lymphatic vessels, attached to holes in the MC (layer 3). Macro molecules and macrophages migrate from mesothelial stomata to the initial lymphatic vessels through holes in the MC. These structures are characteristically found in the diaphragm, omentum, paracolic gutter, pelvic peritoneum, and falciform ligament. The first step of PM is spillage of cancer cells (peritoneal free cancer cells; PFCCs) into the peritoneal cavity from the serosal surface of the primary tumor or cancer cell contamination from lymphatic and blood vessels torn during surgical procedures. After PFCCs adhere to the peritoneal surface, PMs form by three processes, i.e., (1) trans-mesothelial metastasis, (2) trans-lymphatic metastasis, and (3) superficial growing metastasis. Because the intraperitoneal (IP) dose intensity is significantly higher when generated by IP chemotherapy than by systemic chemotherapy, IP chemotherapy has a great role in the treatment of PFCCs, superficial growing metastasis, trans-lymphatic metastasis and in the early stages of trans-mesothelial metastasis. However, an established trans-mesothelial metastasis has its own interstitial tissue and vasculature which generate high interstitial pressure. Accordingly, it is reasonable to treat established trans-mesothelial metastasis by bidirectional chemotherapy from both IP and systemic chemotherapy.

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“…Anoikis resistance (AR) is a prerequisite for hematogenous metastasis [ 65 , 66 ], lymphatic metastasis [ 7 ], and PM of GC [ 67 ]. Several processes contribute to AR development, including promotion of EMT, oncogene activation, adaptation of metabolism, and changes in expression of the integrin family of genes [ 49 , 68 ]. The PI3K/Akt, PTEN/PI3K/NF-kB/FAK, and CXCL12/CXCR4 pathways are associated with anoikis resistance [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

Section: Multistep Processmentioning

confidence: 99%

Molecular Mechanisms and Potential Rationale of Immunotherapy in Peritoneal Metastasis of Advanced Gastric Cancer

Kang

Kim

2022

Biomedicines

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Peritoneal metastasis (PM) is one of the most frequent metastasis patterns of gastric cancer (GC), and the prognosis of patients with PM is very dismal. According to Paget’s theory, disseminated free cancer cells are seeded and survive in the abdominal cavity, adhere to the peritoneum, invade the subperitoneal tissue, and proliferate through angiogenesis. In these sequential processes, several key molecules are involved. From a therapeutic point of view, immunotherapy with chemotherapy combination has become the standard of care for advanced GC. Several clinical trials of newer immunotherapy agents are ongoing. Understanding of the molecular process of PM and the potential rationale of immunotherapy for PM treatment is necessary. Beyond understanding of the molecular aspect of PM, many studies have been conducted on the modality of treatment of PM. Notably, intraperitoneal approaches, including chemotherapy or immunotherapy, have been conducted, because systemic treatment of PM has limitations. In this study, we reviewed the molecular mechanisms and immunologic aspects of PM, and intraperitoneal approaches under investigation for treating PM.

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Anoikis resistant gastric cancer cells promote angiogenesis and peritoneal metastasis through C/EBPβ-mediated PDGFB autocrine and paracrine signaling

Cited by 59 publications

References 59 publications

Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake

Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake

The Development of Peritoneal Metastasis from Gastric Cancer and Rationale of Treatment According to the Mechanism

Molecular Mechanisms and Potential Rationale of Immunotherapy in Peritoneal Metastasis of Advanced Gastric Cancer

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