Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1(+)TIE2(Hi)CXCR4(Hi)) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release. A similar perivascular, M2-related TAM subset was present in human breast carcinomas and bone metastases after chemotherapy. Although a small proportion of M2 TAMs were also present in hypoxic tumor areas, when we genetically ablated their ability to respond to hypoxia via hypoxia-inducible factors 1 and 2, tumor relapse was unaffected. TAMs were the predominant cells expressing immunoreactive CXCR4 in chemotherapy-treated mouse tumors, with the highest levels expressed by MRC1(+) TAMs clustering around the tumor vasculature. Furthermore, the primary CXCR4 ligand, CXCL12, was upregulated in these perivascular sites after chemotherapy, where it was selectively chemotactic for MRC1(+) TAMs. Interestingly, HMOX-1, a marker of oxidative stress, was also upregulated in perivascular areas after chemotherapy. This enzyme generates carbon monoxide from the breakdown of heme, a gas known to upregulate CXCL12. Finally, pharmacologic blockade of CXCR4 selectively reduced M2-related TAMs after chemotherapy, especially those in direct contact with blood vessels, thereby reducing tumor revascularization and regrowth. Our studies rationalize a strategy to leverage chemotherapeutic efficacy by selectively targeting this perivascular, relapse-promoting M2-related TAM cell population.
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PMID:Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy. 2626 31

Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher TIE2 expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B and arrested cells in the G0/G1 phase. Expression of TIE2 also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, TIE2 expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells.
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PMID:TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases. 3226 72