Collagen Remodeling in the Hypoxic Tumor-Mesothelial Niche Promotes Ovarian Cancer Metastasis

Natarajan, Suchitra; Foreman, Kaitlyn M.; Soriano, Michaela I.; Rossen, Ninna S.; Shehade, Hussein; Fregoso, Daniel R.; Eggold, Joshua T.; Krishnan, Venkatesh; Dorigo, Oliver; Krieg, Adam J.; Heilshorn, Sarah C.; Sinha, Subarna; Fuh, Katherine C.; Rankin, Erinn B.

doi:10.1158/0008-5472.can-18-2616

Cited by 94 publications

(101 citation statements)

References 53 publications

(59 reference statements)

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“…Targeting CCR1 in cancer patients to reduce metastasis or induce changes in the tumor microenvironment might lead to anti-tumor immune responses due to reduction of monocytic infiltration. 15,17,[50][51][52][53] . Neutrophil Extracellular Traps (NET) formation provides a premetastatic omental niche conducive for implantation of ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…In this process, mesothelial cells are displaced by ovarian cancer spheroids followed by invasion of cancer cells into the deeper layer of peritoneal tissues 54 . Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion 52 . Further, during ovarian cancer progression, omental adipocytes provide fatty acids as an energy source to ovarian cancer cells 7 .…”

Section: Discussionmentioning

confidence: 99%

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Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1

Krishnan¹,

Tallapragada²,

Schaar

et al. 2020

Commun Biol

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The omentum is the most common site of ovarian cancer metastasis. Immune cell clusters called milky spots are found throughout the omentum. It is however unknown if these immune cells contribute to ovarian cancer metastasis. Here we report that omental macrophages promote the migration and colonization of ovarian cancer cells to the omentum through the secretion of chemokine ligands that interact with chemokine receptor 1 (CCR1). We found that depletion of macrophages reduces ovarian cancer colonization of the omentum. RNA-sequencing of macrophages isolated from mouse omentum and mesenteric adipose tissue revealed a specific enrichment of chemokine ligand CCL6 in omental macrophages. CCL6 and the human homolog CCL23 were both necessary and sufficient to promote ovarian cancer migration by activating ERK1/2 and PI3K pathways. Importantly, inhibition of CCR1 reduced ovarian cancer colonization. These findings demonstrate a critical mechanism of omental macrophage induced colonization by ovarian cancer cells via CCR1 signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1

Krishnan¹,

Tallapragada²,

Schaar

et al. 2020

Commun Biol

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“…Other partners in close contact with collagen involvement in cancer are microRNAs (miRNAs) [125] and exosomes [126]. Moreover, collagen interaction with other ECM molecules including fibronectin, laminin, hyaluronic acid, and MMPs influences cancer cell activity [127]. In addition, hypoxia, which is common in collagen-rich tumors, promotes cancer progression [124].…”

Section: Ecmmentioning

confidence: 99%

Tumor microenvironment complexity and therapeutic implications at a glance

et al. 2020

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The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices.

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“…ECM is composed of collagen, elastin fibrils, proteoglycan, glycosaminoglycan, glycoprotein and protease, which are interconnected to form a dynamic cell regulatory niche and provide structural stability [ 254 ]. Studies have shown that ECM is sustainably remodeled to play an important role in the proliferation, migration, adhesion, invasion and metastasis of tumor cells [ 255 , 256 ]. In intratumoral hypoxia, HIF-1α activates genes encoding collagen prolyl hydroxylases, such as P4HA1 and P4HA2, and collagen prolyl hydroxylases, such as PLOD2 [ 257 ].…”

Section: Role Of Hif-α On Extracellular Matrix Remodeling Through Epimentioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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Collagen Remodeling in the Hypoxic Tumor-Mesothelial Niche Promotes Ovarian Cancer Metastasis

Cited by 94 publications

References 53 publications

Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1

Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1

Tumor microenvironment complexity and therapeutic implications at a glance

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

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