Characterization of the Host Proinflammatory Response to Tumor Cells during the Initial Stages of Liver Metastasis

Khatib, Abdel‐Majid; Auguste, Patrick; Fallavollita, Lucia; Wang, Ni; Samani, Amir; Kontogiannea, Maria; Meterissian, Sarkis; Brodt, Pnina

doi:10.1016/s0002-9440(10)62048-2

Cited by 131 publications

(129 citation statements)

References 36 publications

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“…Recently, it has also been described that metastatic tumor cells are able to induce TNF-a production by Kupffer cells and these latter constitute the major source of TNF-a in tumor cell-inoculated livers. 33 In agreement with the aforementioned observations, our results show that metastatic cancer cells fuse spontaneously in vitro and in vivo. This is in line with another recent report by Lu and Kang showing that organotropisms of metastatic cells can be acquired through spontaneous fusion between cancer cells with bone and lung tropism that eventually generates populations of cells capable of metastasizing to both organs.…”

Section: Discussionsupporting

confidence: 91%

Cell fusion promotes chemoresistance in metastatic colon carcinoma

et al. 2012

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Chemoresistance is an important concern in the treatment of metastatic colon cancer. It may emerge through selection of clones that are inherently resistant from the outset or through mechanisms acquired during treatment. Cell fusion represents an efficient means of rapid phenotypic evolution that make cells with new properties at a rate exceeding that achievable by random mutagenesis. Here, we first identified a number of proteins involved in cell fusion using a shotgun proteomics approach, then we investigated the role of these proteins namely tetraspanin CD81/CD9, ADAM10, GTP-binding protein a13, radixin, myosin regulatory light chain and RhoA in the regulation of colon cancer cell fusion. We also found a previously unrecognized role of ADAM10, Ga13 and RhoA in promoting cell fusion. Finally, we show that the occurrence of cell fusion in a metastatic model of colon carcinoma causes the appearance of cells resistant to both 5-fluorouracil and oxaliplatin. These findings highlight the importance of cell fusion in cancer progression and raise significant implications for overcoming chemoresistance in metastatic colon cancer.

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Section: Discussionsupporting

confidence: 91%

Cell fusion promotes chemoresistance in metastatic colon carcinoma

et al. 2012

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“…Among these, only Sele (E-selectin) mRNA expression was significantly and ectopically induced after tumor inoculation (Fig. S2), which correlated with observations in the liver by other groups (26,27). Notably, Sele mRNA levels at 4 h were significantly lower in the lungs of Apba3 −/− than WT mice (Fig.…”

Section: Apba3 Supports Metastasis Formation Via Induction Of E-selectinsupporting

confidence: 79%

Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

Hara

Nakaoka

Hayashi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Cancer metastasis is intricately orchestrated by both cancer and normal cells, such as endothelial cells and macrophages. Monocytes/macrophages, which are often co-opted by cancer cells and promote tumor malignancy, acquire more than half of their energy from glycolysis even during normoxic conditions. This glycolytic activity is maintained during normoxia by the functions of hypoxia inducible factor 1 (HIF-1) and its activator APBA3. The mechanism by which APBA3 inhibition partially suppresses macrophage function and affects cancer metastasis is of interest in view of avoidance of the adverse effects of complete suppression of macrophage function during therapy. Here, we report that APBA3-deficient mice show reduced metastasis, with no apparent effect on primary tumor growth. APBA3 deficiency in inflammatory monocytes, which strongly express the chemokine receptor CCR2 and are recruited toward chemokine CCL2 from metastatic sites, hampers glycolysis-dependent chemotaxis of cells toward metastatic sites and inhibits VEGFA expression, similar to the effects observed with HIF-1 deficiency. Host APBA3 induces VEGFA-mediated E-selectin expression in the endothelial cells of target organs, thereby promoting extravasation of cancer cells and micrometastasis formation. Administration of E-selectin-neutralizing antibody also abolished host APBA3-mediated metastatic formation. Thus, targeting APBA3 is useful for controlling metastatic niche formation by inflammatory monocytes.APBA3/Mint3 | macrophage | metastasis C ancer metastasis comprises multiple processes of neoplastic progression, termed the "invasion-metastasis cascade" (1, 2). Thousands of circulating tumor cells (CTCs) can be released from invasive primary tumors; however, most patients develop only a few metastases, suggesting that metastatic initiation processes (such as extravasation and colonization at distant organs) are quite inefficient but key for controlling metastatic cancer diseases. Unlike at primary sites, single or small groups of disseminated CTCs encounter large numbers of normal cells in their new environments, which determines their survival and metastatic efficiency, as shown by studies with genetically engineered mouse models (3-5).Macrophages are myeloid cells that are co-opted essentially to foster tumor progression and metastasis. The functions of tumorassociated macrophages include angiogenesis, suppression of antitumor immune responses, chemoresistance, and metastasis; these are considered novel targets for cancer therapy (6-10). Monocytes (i.e., macrophage precursors) are characterized by the surface molecules CD11b and CD115, and comprise at least two subsets: Gr-1 + (Ly-6C high )CCR2 + CX3CR1 low inflammatory monocytes (IMs) and Gr-1 low (Ly-6C low )CCR2 low CX3CR1 high resident monocytes (RMs) (11). Their recruitment from the bone marrow (BM) to peripheral tissues is mediated mainly by chemokine-chemokine receptor complexes such as the CCL2/CCR2 system (12, 13). Even in metastatic cascades, the CCL2-CCR2 axis is a key pathway for IM ...

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“…Tumor cells are known to upregulate TNF-a, which in turn increases endothelial cell expression of adhesion molecules (e.g. P-selectin, E-selectin and VCAM-1) that facilitate tumor cell interaction with the endothelium leading to extravasation (Khatib et al, 1999;Ding et al, 2001;Kitakata et al, 2002). The higher hepatic TNF-a levels in timp-3 À/À mice may upregulate adhesion molecules and the attachment of EL-4 lymphoma cells to hepatic endothelium, facilitating extravasation.…”

Section: Discussionmentioning

confidence: 99%

Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

et al. 2006

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Identifying versatile inhibitors of metastasis that operate in multiple sites against distinct cancer cell types is important for designing novel therapeutics for metastasis. We show that multiple tissues of timp-3 À/À mice are more susceptible to metastatic colonization. Overall, a 5-14-fold increase in liver and kidney colonization occurred by EL-4 lymphoma cells, and a twofold increase upon targeting B16F10 melanoma cells to the bone or lung of timp-3 À/À mice. There was a general lack of macrophage or neutrophil localization to metastases in the liver, kidney and lung, and of osteoclasts to bone in both genotypes. Analysis of lung showed that proliferation or angiogenesis were unaltered within the metastatic colonies. Lung-trap assays revealed that initial tumor cell trapping was similar in the lung vasculature of timp-3 À/À and wild-type mice. However, more tumor cells were found in timp-3 À/À lungs at 48 and 96 h after tumor cell injection indicating more efficient extravasation and initial proliferation. Activation of pro-MMP-2 was greater in timp-3 À/À lungs at these time points. These data demonstrate TIMP-3 functions to inhibit metastatic dissemination of diverse cancer cells to multiple organs. TIMP-3 regulates MMP-2 activation to limit tumor cell extravasation and subsequent colonization of the lung, without augmenting inflammatory cell response.

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Characterization of the Host Proinflammatory Response to Tumor Cells during the Initial Stages of Liver Metastasis

Cited by 131 publications

References 36 publications

Cell fusion promotes chemoresistance in metastatic colon carcinoma

Cell fusion promotes chemoresistance in metastatic colon carcinoma

Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

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