The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

Harney, Allison S.; Karagiannis, George S.; Pignatelli, Jeanine; Smith, Bryan D.; Kadioglu, Ece; Wise, Scott; Hood, Molly M.; Kaufman, Michael D.; Leary, Cynthia B.; Lu, Wei; Al-Ani, Gada; Chen, Xiaoming; Entenberg, David; Oktay, Maja H.; Wang, Yarong; Chun, Lawrence; Palma, Michele De; Jones, Joan G.; Flynn, Daniel L.; Condeelis, John S.

doi:10.1158/1535-7163.mct-17-0241

Cited by 114 publications

(131 citation statements)

References 77 publications

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“…For example, a conditional VEGFA‐KO mouse model of breast carcinoma in which VEGFA expression was specifically deleted in the monocyte/macrophage lineage, results in breast tumors with unaffected TMEM assembly, but impaired VEGF‐dependent vascular wall disruption and cancer cell dissemination. These observations suggest that specific inhibitors targeting TIE2 HIGH macrophages, such as rebastinib, could be potentially used along with chemotherapy to suppress metastatic dissemination and growth, respectively …”

Section: Tumor‐associated Macrophages In Cancer Metastasismentioning

confidence: 99%

“…Further IHC/IF analyses on TMEM sites have indicated that each functional TMEM site is composed of a perivascular macrophage expressing high levels of TIE2, VEGFA, and mannose receptor (MRC1), suggesting they could represent a distinct subpopulation of M2 or M2‐like TAMs. TIE2 HIGH VEGFA HIGH MRC1 HIGH macrophages have been intensely studied as they can induce pro‐angiogenic, pro‐metastatic, immunosuppressive, and chemoresistant niches in a context‐dependent manner. For example, using the well‐described MMTV‐PyMT mouse model of breast carcinoma, it was demonstrated that VEGFA secreted by the TIE2 HIGH macrophage on TMEM sites disassembles the underlying vascular junction proteins, zonula occludens‐1 (ZO1) and vascular‐endothelial cadherin (VE‐CAD), exposing a paracellular passage that metastasizing tumor cells use to escape into the circulation .…”

Section: Tumor‐associated Macrophages In Cancer Metastasismentioning

confidence: 99%

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The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Sanchez

Borriello

Entenberg

et al. 2019

Journal of Leukocyte Biology

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Macrophages represent a heterogeneous group of cells, capable of carrying out distinct functions in a variety of organs and tissues. Even within individual tissues, their functions can vary with location. Tumor‐associated macrophages (TAMs) specialize into three major subtypes that carry out multiple tasks simultaneously. This is especially true in the context of metastasis, where TAMs establish most of the cellular and molecular prerequisites for successful cancer cell dissemination and seeding to the secondary site. Perivascular TAMs operate in the perivascular niche, where they promote tumor angiogenesis and aid in the assembly of intravasation sites called tumor microenvironment of metastasis (TMEM). Streaming TAMs co‐migrate with tumor cells (irrespective of the perivascular niche) and promote matrix remodeling, tumor cell invasiveness, and an immunosuppressive local microenvironment. Premetastatic TAMs are recruited to the premetastatic niche, where they can assist in tumor cell extravasation, seeding, and metastatic colonization. The dynamic interplay between TAMs and tumor cells can also modify the ability of the latter to resist cytotoxic chemotherapy (a phenotype known as environment‐mediated drug resistance) and induce chemotherapy‐mediated pro‐metastatic microenvironmental changes. These observations suggest that future therapeutics should be designed to target TAMs with the aim of suppressing the metastatic potential of tumors and rendering chemotherapy more efficient.

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Section: Tumor‐associated Macrophages In Cancer Metastasismentioning

confidence: 99%

Section: Tumor‐associated Macrophages In Cancer Metastasismentioning

confidence: 99%

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Sanchez

Borriello

Entenberg

et al. 2019

Journal of Leukocyte Biology

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“…The mechanisms underlying these intravasation events have been well elucidated [42,54,57–59] and can be directly inhibited in vitro and in vivo by blocking their underlying pathways [42,58–60]. …”

Section: Hypoxia Motility and Directionality In The Primary Tumormentioning

confidence: 99%

The Different Routes to Metastasis via Hypoxia-Regulated Programs

Nobre

Entenberg

Wang

et al. 2018

Trends in Cell Biology

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Hypoxia is linked to metastasis; however, how it affects metastatic progression is not clear due to limited consensus in the literature. We posit that this lack of consensus is due to hypoxia being studied using different approaches, such as in vitro, primary tumor, or metastasis assays in an isolated manner. Here, we review the pros and cons of in vitro hypoxia assays, highlight in vivo studies that inform on physiological hypoxia, and review the evidence that primary tumor hypoxia might influence the fate of disseminated tumor cells (DTCs) in secondary organs. Our analysis suggests that consensus can be reached by using in vivo methods of study, which also allow better modeling of how hypoxia affects DTC fate and metastasis.

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Section: George S Karagiannis John S Condeelis and Maja H Oktaymentioning

confidence: 99%

“…For instance, the selective Tie2 inhibitor rebastinib inhibits TMEM function by inhibiting Tie2 on the TMEM macrophage to prevent VEGF-dependent vascular permeability [8]. The use of rebastinib significantly reduces the number of TMEMdependent circulating tumor cells in the blood and the number of disseminating tumor cells in the lungs [3], and significantly increases overall survival of paclitaxeltreated mice [8], suggesting that Tie2 inhibition of TMEM alone could confer reversal of the chemotherapy-induced prometastatic tumor microenvironment [3]. Results similar to that obtained with rebastinib inhibition of chemotherapy-induced prometastatic changes have been phenocopied after genetic ablation of the MENA gene in the MMTV-PyMT mouse model, which spontaneously develops metastatic breast tumors [3], consistent with the finding that increased MENA INV expression is a chemotherapy-induced prometastatic change, critical for cancer cell dissemination [3].…”

Section: George S Karagiannis John S Condeelis and Maja H Oktaymentioning

confidence: 99%

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2017

Oncotarget

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Randomized prospective studies have indicated that the addition of taxanes into the preoperative, also called neoadjuvant chemotherapy, regimen of breast cancer patients increases the rate of pathological complete response (pCR), but paradoxically does not improve overall survival [1]. Preclinical findings in mouse models of breast and other types of carcinomas suggest that this may be the result of chemotherapy-induced proangiogenic and prometastatic changes in the microenvironment of the primary tumor, triggered as a response to cytotoxic tissue damage [2][3][4]. It has been well-established that neoadjuvant chemotherapy induces new blood vessel formation as a result of bone marrow progenitor cell infiltration into the primary tumor, including endothelial cell precursors and monocyte/macrophage progenitors, which subsequently provide sufficient support for tumor regrowth [4]. However, the effects of neoadjuvant chemotherapy on tumor metastasis were underexplored until recently.Indeed, the perivascular proangiogenic macrophages are also capable of assembling specialized microanatomical structures called tumor microenvironment of metastasis (TMEM), known to regulate vascular permeability and cancer cell intravasation and dissemination [5]. In particular, perivascular macrophages expressing high levels of the angiopoietin receptor Tie2 (i.e. Tie2Hi macrophages) secrete high concentrations of vascular endothelial growth factor (VEGF) locally, which in turn disrupts the underlying endothelial junctions and promotes vascular permeability and tumor cell intravasation. Our group has shown that neoadjuvant chemotherapy mobilizes such Tie2Hi macrophages in the primary tumor microenvironment, which significantly promotes TMEM assembly and breast cancer cell dissemination to metastatic sites [3]. Chemotherapy-induced TMEM assembly and metastasis has been further corroborated by another research group using multiple models of breast carcinoma [6].Neoadjuvant chemotherapy may not only create a metastasis-promoting perivascular microenvironment as described above, but it could also directly affect the phenotypic characteristics and behavior of metastasizing cancer cells. For instance, it has been shown that direct contact of tumor cells and macrophages, an event likely occurring near and at TMEM sites, results in the expression of MENA INV , the invasive isoform of the actin-regulatory protein mammalian enabled (MENA) [5]. Indeed, it has been documented that neoadjuvant chemotherapy in preclinical models of breast cancer and in residual tumors from patients after completion of neoadjuvant chemotherapy can significantly increase MENA INV -expression [3,7]. However, the relative amount of Mena INV expression resulting from macrophage-cancer cell contact [3], as opposed to the selection of MENA INV drug-resistant cells [7], remains to be elucidated. In either case, an increase of MENA INV cancer cells in the primary tumor generates a highly invasive and migratory cancer cell subpopulation, capable of TMEM-dependent disseminatio...

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The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

Cited by 114 publications

References 77 publications

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

The Different Routes to Metastasis via Hypoxia-Regulated Programs

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