RESUMO
Given the importance of menstrual blood in the pathogenesis of endometriosis and the multifunctional roles of menstrual mesenchymal stem cells (MenSCs) in regenerative medicine, this issue has gained prominence in the scientific community. Moreover, recent reviews highlight how robust the integrated assessment of omics data are for endometriosis. To our knowledge, no study has applied the multi-omics approaches to endometriosis MenSCs. This is a case-control study at a university-affiliated hospital. MenSCs transcriptome and proteome data were obtained by RNA-seq and UHPLC-MS/MS detection. Among the differentially expressed proteins and genes, we emphasize ATF3, ID1, ID3, FOSB, SNAI1, NR4A1, EGR1, LAMC3, and ZFP36 genes and MT2A, TYMP, COL1A1, COL6A2, and NID2 proteins that were already reported in the endometriosis. Our functional enrichment analysis reveals integrated modulating signaling pathways such as epithelial-mesenchymal transition (↑) and PI3K signaling via AKT to mTORC1 (↓ in proteome), mTORC1 signaling, TGF beta signaling, TNFA signaling via NFkB, IL6 STAT3 signaling, and response to hypoxia via HIF1A targets (↑ in transcriptome). Our findings highlight primary changes in the endometriosis MenSCs, suggesting that the chronic inflammatory endometrial microenvironment can modulate these cells, providing opportunities for endometriosis etiopathogenesis. Moreover, they identify challenges for future research leveraging knowledge for regenerative and precision medicine in endometriosis.
Assuntos
Endometriose , Células-Tronco Mesenquimais , Estudos de Casos e Controles , Proliferação de Células , Endometriose/patologia , Feminino , Humanos , Interleucina-6 , Laminina , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Menstruação , Células-Tronco Mesenquimais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteoma , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espectrometria de Massas em Tandem , Transcriptoma , Fator de Crescimento Transformador beta/genéticaRESUMO
Here, we describe the case of a patient diagnosed with locally advanced breast cancer 8 years ago. Her treatment course was neoadjuvant chemotherapy, followed by mastectomy and then adjuvant radiotherapy and trastuzumab (TTZ). During the use of adjuvant targeted therapy, an incidental pregnancy was diagnosed. Four years later, she developed bone and cerebral metastases, and since then, she has received courses of TTZ, capecitabine, lapatinib, and radiotherapy with intermittent control of the disease. Her 7-year-old son presents a normal physical and long-term neurological developmental curve according to specialized evaluation. This case is unique for several reasons: the patient received the highest dose of TTZ yet described during pregnancy (4400 mg); there has been a long period of disease-free survival after treatment for locally advanced breast cancer and long overall survival despite successive disease progressions during the metastatic phase of the disease (97 months), and there was a monitored pediatric follow-up period (7 years).
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Trastuzumab/uso terapêutico , Adulto , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Gravidez , Complicações Neoplásicas na Gravidez/patologiaRESUMO
Invasive lobular carcinoma (ILC) and lobular neoplasia (LN) are two distinct conditions that still pose challenges regarding to their classification, diagnosis and management. Although they share similar cellular characteristics, such as discohesive neoplastic cells and absence of e-cadherin staining, they represent completely different conditions. LN encompasses atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), which are currently considered risk factors and non-obligatory precursors of breast neoplasia. These lesions are diagnosed as incidental findings in percutaneous biopsies or appear as non-specific clusters of punctate calcifications in mammograms. ILC is the second most common breast malignancy and has typical histological features, such as infiltrative growth and low desmoplasia. These histological features are reflected in imaging findings and constitute the reasons for typical subtle mammographic features of ILC, as architectural distortion or focal asymmetries. Ultrasonography (US) may detect almost 75 % of the ILCs missed by mammography and represents the modality of choice for guiding biopsies. Magnetic resonance imaging (MRI) exhibits a high sensitivity for the diagnosis of ILC and for detecting synchronous lesions. Teaching Points ⢠LN includes ALH and LCIS, risk factors and non-obligatory precursors of breast cancer.⢠Absence of e-cadherin staining is crucial for differentiation among ductal and lobular lesions. ⢠ILC has typical histological features, such as infiltrative growth and low desmoplasia. ⢠Mammographic features of ILC are often subtle and reflect the histological features. ⢠MRI exhibits a high sensitivity for the diagnosis of ILC and for detecting synchronous lesions.
RESUMO
Breast cancer is a leading cause of neoplasia-associated death in women worldwide. Regulatory T (Treg) and Th17 cells are enriched within some tumors, but the role these cells play in invasive ductal carcinoma (IDC) of the breast is unknown. We show that CD25(+) CD4(+) T cells from PBMCs and tumor express high levels of Foxp3, GITR, CTLA-4, and CD103, indicating that tumor-infiltrating Treg cells are functional and possibly recruited by CCL22. Additionally, we observed upregulation of Th17-related molecules (IL-17A, RORC, and CCR6) and IL-17A produced by tumor-infiltrating CD4(+) and CD8(+) T lymphocytes. The angiogenic factors CXCL8, MMP-2, MMP-9, and vascular endothelial growth factor detected within the tumor are possibly induced by IL-17 and indicative of poor disease prognosis. Treg and Th17 cells were synchronically increased in IDC patients, with positive correlation between Foxp3, IL-17A, and RORC expression, and associated with tumor aggressiveness. Therefore, Treg and Th17 cells can affect disease progression by Treg-cell-mediated suppression of the effector T-cell response, as indicated by a decrease in the proliferation of T cells isolated from PBMCs of IDC patients and induction of angiogenic factors by IL-17-producing Th17. The understanding of regulation of the Treg/Th17 axis may result in novel perspectives for the control of invasive tumors.
Assuntos
Neoplasias da Mama/imunologia , Carcinoma Ductal/imunologia , Interleucina-17/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Antígenos CD/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal/patologia , Proliferação de Células , Transformação Celular Neoplásica/imunologia , Quimiocina CCL22/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Humanos , Interleucina-17/genética , Invasividade Neoplásica , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores CCR6/metabolismo , Células Tumorais Cultivadas , Regulação para CimaRESUMO
BACKGROUND: Neoadjuvant chemotherapy has been considered the standard care in locally advanced breast cancer. However, about 20% of the patients do not benefit from this clinical treatment and, predictive factors of response were not defined yet. This study was designed to evaluate the importance of biological markers to predict response and prognosis in stage II and III breast cancer patients treated with taxane and anthracycline combination as neoadjuvant setting. METHODS: Sixty patients received preoperative docetaxel (75 mg/m2) in combination with epirubicin (50 mg/m2) in i.v. infusion in D1 every 3 weeks after incisional biopsy. They received adjuvant chemotherapy with CMF or FEC, attaining axillary status following definitive breast surgery. Clinical and pathologic response rates were measured after preoperative therapy. We evaluated the response rate to neoadjuvant chemotherapy and the prognostic significance of clinicopathological and immunohistochemical parameters (ER, PR, p51, p21 and HER-2 protein expression). The median patient age was 50.5 years with a median follow up time 48 months after the time of diagnosis. RESULTS: Preoperative treatment achieved clinical response in 76.6% of patients and complete pathologic response in 5%. The clinical, pathological and immunohistochemical parameters were not able to predict response to therapy and, only HER2 protein overexpression was associated with a decrease in disease free and overall survival (P = 0.0007 and P = 0.003) as shown by multivariate analysis. CONCLUSION: Immunohistochemical phenotypes were not able to predict response to neoadjuvant chemotherapy. Clinical response is inversely correlated with a risk of death in patients submitted to neoadjuvant chemotherapy and HER2 overexpression is the major prognostic factor in stage II and III breast cancer patients treated with a neoadjuvant docetaxel and epirubicin combination.