Macrophages Promote Circulating Tumor Cell–Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients

Rafat, Marjan; Aguilera, Todd A.; Vilalta, Marta; Bronsart, Laura L.; Soto, Luis Alonso Leyva; Eyben, Rie von; Golla, Meghana; Ahrari, Yasaman; Melemenidis, Stavros; Afghahi, Anosheh; Jenkins, Melissa J.; Kurian, Allison W.; Horst, Kathleen C.; Giaccia, Amato J.; Graves, Edward E.

doi:10.1158/0008-5472.can-17-3623

Cited by 40 publications

(59 citation statements)

References 49 publications

(46 reference statements)

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“…Among these, Col I is considered the most promising osteospecific marker in the literature concerning human OSA (31), and was therefore a logical choice to assess in canine OSA. Both canine OSA cell lines were indeed highly positive with antibodies to Col I, consistent with the fundamental characteristic of collagen production by this tumor histotype (41,42). Osteocalcin was detected in most but not all tumor cell lines, which is in agreement with findings from immunohistochemical assays of primary tumor tissue (40,42), and studies of human OSA (31).…”

Section: Discussionsupporting

confidence: 83%

“…Both canine OSA cell lines were indeed highly positive with antibodies to Col I, consistent with the fundamental characteristic of collagen production by this tumor histotype (41,42). Osteocalcin was detected in most but not all tumor cell lines, which is in agreement with findings from immunohistochemical assays of primary tumor tissue (40,42), and studies of human OSA (31). However, analysis of blood samples from clinical patients indicated variable Col I and rare OC detection among CTCs.…”

Section: Discussionsupporting

confidence: 83%

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Flow Cytometric Detection of Circulating Osteosarcoma Cells in Dogs

et al. 2019

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Osteosarcoma (OSA) is a malignant tumor of middle-aged dogs and adolescent humans. The clinical outcome of OSA has not improved over more than three decades, and dogs typically succumb to metastatic disease within 6 months despite tumor resection through limb amputation and adjuvant chemotherapy. Therefore, undetectable tumor cells with potential to form metastases are present at diagnosis. An assay to identify canine immortalized and primary OSA cells through flow cytometric detection of intracellular collagen 1 (Col I) and osteocalcin was optimized, and applied to blood samples from tumorbearing dogs for detection of circulating tumor cells (CTCs). Spiking variable number of OSA cells into normal dog blood recovered 50-60% of Col I positive cells with high forward and variable side light scatter. An algorithm to exclude nonviable, doublet, and autofluorescent cells was applied to sequential blood samples from three dogs obtained prior to and after limb amputation, and at approximately, triweekly intervals over 121, 142, and 183 days of chemotherapy, respectively. Dogs had >100 CTC/10 6 leukocytes prior to amputation, variably frequent CTC during chemotherapy, and an increase up to 4,000 CTC/10 6 leukocytes within 4 weeks before overt metastases or death. Sorted CTCs were morphologically similar to direct tumor aspirates and positive for Col I. Although preliminary, findings suggest that CTCs are frequent in canine OSA, more numerous than carcinoma CTC in humans, and that an increase in CTC frequency may herald clinical deterioration. This assay may enable enumeration and isolation of OSA CTC for prognostic and functional studies, respectively. OSTEOSARCOMA (OSA) is a primary bone cancer that is common in middle-aged to older, large breed dogs, and less common in humans, where children and young adults are most often affected. Therapy consisting of limb amputation or limbsparing tumor resection followed by chemotherapy (typically platinum or doxorubicin-based) is the gold standard, but the clinical outcome of OSA in dogs and humans remains poor (1-3). Dogs with OSA of the appendicular skeleton treated with amputation and chemotherapy had median survival times (STs) of 235-540 days (4), while in humans 5-year survival has been stagnant at about 60% (5). Although the median ST is relatively homogeneous, the range of ST in dogs with OSA treated identically varies from 2 to >30 months, illustrating that there is extensive heterogeneity in tumor biology and/or host response (6-8). Metastatic disease is the usual cause of spontaneous death or euthanasia, but fewer than 10% of dogs have radiographic evidence of metastasis at the time of diagnosis (2).Computed tomography also lacks sensitivity for identifying metastases, and histologic grading schemes for canine OSA poorly predict biological behavior (9-11).

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 83%

Flow Cytometric Detection of Circulating Osteosarcoma Cells in Dogs

et al. 2019

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“…TAM are an important component of the TME that play a role in angiogenesis, metastasis, and tumor malignancy. 43,47 Our previous studies have confirmed that TAM are correlated with tamoxifen resistance in patients with breast cancer. 22 In the present study, we investigated the mechanisms underlying TAM-mediated endocrine resistance in breast cancer cells.…”

Section: Discussionmentioning

confidence: 74%

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

et al. 2019

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Abbreviations: CCL2, CC-chemokine ligand 2; CM, conditioned medium; ER, estrogen receptor; MCP-1, monocyte chemoattractant protein 1; MR, tumor-associated macrophage from a tamoxifen-resistant tumor microenvironment; MS, tumor-associated macrophage from a tamoxifen-sensitive tumor microenvironment; PFS, progression-free survival; TAM, tumor-associated macrophage; TME, tumor microenvironment. AbstractBreast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor-associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine-resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen-sensitive (MCF7-S) or -resistant (MCF7-R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC-chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor-positive breast cancer. We found that macrophages cultured in the CM of MCF7-S and MCF7-R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression-free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrineresistant breast cancer.

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“…Before cancer cells, TAMs will infiltrate into irradiated normal tissues under radiotherapeutic stress. Then, TAMs secrete soluble factors such as inflammatory protein 1 beta to recruit cancer cells, promoting cancer metastasis and recurrence following radiotherapy [91]. Soluble factors from TAMs also have the potential to induce the expression of cytidine deaminase (a metabolism enzyme) in cancer cells, which reduces the efficacy of gemcitabine [90].…”

Section: Favorable Tumor Microenvironmentmentioning

confidence: 99%

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

et al. 2020

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Circular RNAs (circRNAs), one type of non-coding RNA, were initially misinterpreted as nonfunctional products of pre-mRNA mis-splicing. Currently, circRNAs have been proven to manipulate the functions of diverse molecules, including non-coding RNAs, mRNAs, DNAs and proteins, to regulate cell activities in physiology and pathology. Accumulating evidence indicates that circRNAs play critical roles in tumor genesis, development, and sensitivity to radiation and chemotherapy. Radiotherapy and chemotherapy are two primary types of intervention for most cancers, but their therapeutic efficacies are usually retarded by intrinsic and acquired resistance. Thus, it is urgent to develop new strategies to improve therapeutic responses. To achieve this, clarification of the underlying mechanisms affecting therapeutic responses in cancer is needed. This review summarizes recent progress and mechanisms of circRNAs in cancer resistance to radiation and chemotherapy, and it discusses the limitations of available knowledge and potential future directions.

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Macrophages Promote Circulating Tumor Cell–Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients

Cited by 40 publications

References 49 publications

Flow Cytometric Detection of Circulating Osteosarcoma Cells in Dogs

Flow Cytometric Detection of Circulating Osteosarcoma Cells in Dogs

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

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