ABSTRACT
In the metastasis-targeted organs, angiogenesis is essential for the progression of dormant micrometastases to rapidly growing and clinically overt lesions. However, we observed changes suggesting angiogenic switching in the mouse lungs prior to arrival of tumor cells (i.e., in the premetastatic niche) in the models of breast carcinoma. This angiogenic switching appears to be caused by myeloid-derived suppressor cells recruited to the premetastatic lungs through complement C5a receptor 1 signaling. These myeloid cells are known to secrete several proangiogenic factors in tumors, including IL-1ß and matrix metalloproteinase-9, and we found upregulation of these genes in the premetastatic lungs. Blockade of C5a receptor 1 synergized with antiangiogenic Listeria monocytogenes-based vaccines to decrease the lung metastatic burden by reducing vascular density and improving antitumor immunity in the lungs. This was mediated even when growth of primary breast tumors was not affected by these treatments. This work provides initial evidence that angiogenesis contributes to the premetastatic niche in rapidly progressing cancers and that inhibiting this process through immunotherapy is beneficial for reducing or even preventing metastasis.
Subject(s)
Cancer Vaccines/administration & dosage , Lung Neoplasms/therapy , Mammary Neoplasms, Experimental/therapy , Myeloid-Derived Suppressor Cells/immunology , Neovascularization, Pathologic/therapy , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Animals , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Cell Line, Tumor , Combined Modality Therapy/methods , Complement C5a/immunology , Complement C5a/metabolism , Female , Humans , Immunotherapy/methods , Listeria monocytogenes/immunology , Lung/blood supply , Lung/immunology , Lung/pathology , Lung Neoplasms/blood supply , Lung Neoplasms/immunology , Lung Neoplasms/secondary , Mammary Neoplasms, Experimental/immunology , Mammary Neoplasms, Experimental/pathology , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Knockout , Myeloid-Derived Suppressor Cells/metabolism , Neoplasm Metastasis/immunology , Neoplasm Metastasis/therapy , Neovascularization, Pathologic/immunology , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Receptor, Anaphylatoxin C5a/genetics , Receptor, Anaphylatoxin C5a/metabolism , Tumor Microenvironment/immunologyABSTRACT
Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event. This binding induces the transactivation of Rheb. The identified NRE2 and NRE3 on the Rheb promoter are important to Notch-dependent promoter activity. Notch cooperates with Rheb to block cell differentiation via similar mechanisms in mouse models of TSC. Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads to the formation of kidney cysts, renal intraepithelial neoplasia, and invasive papillary renal carcinoma.
