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A substantial percentage of the population remains at risk for cervical cancer due to pre-existing human papillomavirus (HPV) infections, despite prophylactic vaccines. Early diagnosis and treatment are crucial for better disease outcomes. The development of new treatments heavily relies on suitable preclinical model systems. Recently, we established a mouse papillomavirus (MmuPV1) model that is relevant to HPV genital pathogenesis. In the current study, we validated the use of Papanicolaou (Pap) smears, a valuable early diagnostic tool for detecting HPV cervical cancer, to monitor disease progression in the MmuPV1 mouse model. Biweekly cervicovaginal swabs were collected from the MmuPV1-infected mice for viral DNA quantitation and cytology assessment. The Pap smear slides were evaluated for signs of epithelial cell abnormalities using the 2014 Bethesda system criteria. Tissues from the infected mice were harvested at various times post-viral infection for additional histological and virological assays. Over time, increased viral replication was consistent with higher levels of viral DNA, and it coincided with an uptick in epithelial cell abnormalities with higher severity scores noted as early as 10 weeks after viral infection. The cytological results also correlated with the histological evaluation of tissues harvested simultaneously. Both immunocompromised and immunocompetent mice with squamous cell carcinoma (SCC) cytology also developed vaginal SCCs. Notably, samples from the MmuPV1-infected mice exhibited similar cellular abnormalities compared to the corresponding human samples at similar disease stages. Hence, Pap smear screening proves to be an effective tool for the longitudinal monitoring of disease progression in the MmuPV1 mouse model. IMPORTANCE: Papanicolaou (Pap) smear has saved millions of women's lives as a valuable early screening tool for detecting human papillomavirus (HPV) cervical precancers and cancer. However, more than 200,000 women in the United States alone remain at risk for cervical cancer due to pre-existing HPV infection-induced precancers, as there are currently no effective treatments for HPV-associated precancers and cancers other than invasive procedures including a loop electrosurgical excision procedure (LEEP) to remove abnormal tissues. In the current study, we validated the use of Pap smears to monitor disease progression in our recently established mouse papillomavirus model. To the best of our knowledge, this is the first study that provides compelling evidence of applying Pap smears from cervicovaginal swabs to monitor disease progression in mice. This HPV-relevant cytology assay will enable us to develop and test novel antiviral and anti-tumor therapies using this model to eliminate HPV-associated diseases and cancers.
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Modelos Animais de Doenças , Teste de Papanicolaou , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Animais , Feminino , Camundongos , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Detecção Precoce de Câncer/métodos , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , DNA Viral/genética , Esfregaço Vaginal , Humanos , Estudos LongitudinaisRESUMO
Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell-specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.
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Antígenos B7 , Linfócitos T CD8-Positivos , Glicoproteínas de Membrana , Microambiente Tumoral , Animais , Humanos , Camundongos , Antígenos B7/imunologia , Antígenos B7/genética , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/genética , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: The role of immune cells in collagen degradation within the tumor microenvironment (TME) is unclear. Immune cells, particularly tumor-infiltrating lymphocytes (TILs), are known to alter the extracellular matrix, affecting cancer progression and patient survival. However, the quantitative evaluation of the immune modulatory impact on collagen architecture within the TME remains limited. METHODS: We introduce CollaTIL, a computational pathology method that quantitatively characterizes the immune-collagen relationship within the TME of gynecologic cancers, including high-grade serous ovarian (HGSOC), cervical squamous cell carcinoma (CSCC), and endometrial carcinomas. CollaTIL aims to investigate immune modulatory impact on collagen architecture within the TME, aiming to uncover the interplay between the immune system and tumor progression. RESULTS: We observe that an increased immune infiltrate is associated with chaotic collagen architecture and higher entropy, while immune sparse TME exhibits ordered collagen and lower entropy. Importantly, CollaTIL-associated features that stratify disease risk are linked with gene signatures corresponding to TCA-Cycle in CSCC, and amino acid metabolism, and macrophages in HGSOC. CONCLUSIONS: CollaTIL uncovers a relationship between immune infiltration and collagen structure in the TME of gynecologic cancers. Integrating CollaTIL with genomic analysis offers promising opportunities for future therapeutic strategies and enhanced prognostic assessments in gynecologic oncology.
The role of cells that are part of our immune system in altering the structure of the protein collagen within cancers is not fully understood, particularly within cancers that affect women such as ovarian, cervical and uterine cancers. Here, we developed a computer-based method called CollaTIL to explore how immune cells influence collagen in these tumors and affect their growth. We found that a higher presence of immune cells leads to less organized collagen in the tumor. Conversely, when there are fewer immune cells, the collagen tends to be more structured. Additionally, CollaTIL identifies patterns that predict patient outcomes in these cancers. These findings not only enhance our understanding of tumor biology but also may be useful in helping clinicians to predict which patients are at risk of their disease progressing.
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Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.
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Células Supressoras Mieloides , Neoplasias , Animais , Humanos , Camundongos , Camundongos Knockout , Células Mieloides/metabolismo , Neoplasias/patologia , Poliaminas/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos TRESUMO
Endometrial cancer (EC) disproportionately affects African American (AA) women in terms of progression and death. In our study, we sought to employ computerized image and bioinformatic analysis to tease out morphologic and molecular differences in EC between AA and European-American (EA) populations. We identified the differences in immune cell spatial patterns between AA and EA populations with markers of tumor biology, including histologic and molecular subtypes. The models performed best when they were trained and validated using data from the same population. Unsupervised clustering revealed a distinct association between immune cell features and known molecular subtypes of endometrial cancer that varied between AA and EA populations. Our genomic analysis revealed two distinct and novel gene sets with mutations associated with improved prognosis in AA and EA patients. Our study findings suggest the need for population-specific risk prediction models for women with endometrial cancer.
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The number of Endometrial Carcinoma (EC) diagnoses is projected to increase substantially in coming decades. Although most ECs have a favorable prognosis, the aggressive, non-endometrioid subtypes are disproportionately concentrated in Black women and spread rapidly, making treatment difficult and resulting in poor outcomes. Therefore, this study offers an exploratory spatial epidemiological investigation of EC patients within a U.S.-based health system's institutional cancer registry (n = 1748) to search for and study geographic patterns. Clinical, demographic, and geographic characteristics were compared by histotype using chi-square tests for categorical and t-tests for continuous variables. Multivariable logistic regression evaluated the impact of risks on these histotypes. Cox proportional hazard models measured risks in overall and cancer-specific death. Cluster detection indicated that patients with the EC non-endometrioid histotypes exhibit geographic clustering in their home address, such that congregate buildings can be identified for targeted outreach. Furthermore, living in a high social vulnerability area was independently associated with non-endometrioid histotypes, as continuous and categorical variables. This study provides a methodological framework for early, geographically targeted intervention; social vulnerability associations require further investigation. We have begun to fill the knowledge gap of geography in gynecologic cancers, and geographic clustering of aggressive tumors may enable targeted intervention to improve prognoses.
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Neoplasias do Endométrio , População Negra , Neoplasias do Endométrio/patologia , Endométrio/patologia , Feminino , Humanos , Modelos de Riscos ProporcionaisRESUMO
Cyclin D1 is a regulatory subunit of -Cyclin Dependent Kinases 4 and 6 (CDK4/6) and regulates progression from G1 to S phase of the cell cycle. Dysregulated cyclin D1-CDK4/6 contributes to abnormal cell proliferation and tumor development. Phosphorylation of threonine 286 of cyclin D1 is necessary for ubiquitin-dependent degradation. Non-phosphorylatable cyclin D1 mutants are stabilized and concentrated in the nucleus, contributing to genomic instability and tumor development. Studies investigating the tumor-promoting functions of cyclin D1 mutants have focused on the use of artificial promoters to drive the expression which unfortunately may not accurately reflect tumorigenic functions of mutant cyclin D1 in cancer development. We have generated a conditional knock-in mouse model where cyclin D1T286A is expressed under the control of its endogenous promoter following Cre-dependent excision of a lox-stop-lox sequence. Acute expression of cyclin D1T286A following tamoxifen-inducible Cre recombinase triggers inflammation, lymphocyte abnormality and ultimately mesenteric tumors in the intestine. Tissue-specific expression of cyclin D1T286A in the uterus and endometrium cooperates with Pten loss to drive endometrial hyperplasia and cancer. Mechanistically, cyclin D1T286A mutant activates NF-κB signaling, augments inflammation, and contributes to tumor development. These results indicate that mutation of cyclin D1 at threonine 286 has a critical role in regulating inflammation and tumor development.
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Carcinoma , Ciclina D1 , Hiperplasia Endometrial , PTEN Fosfo-Hidrolase , Animais , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Feminino , Humanos , Inflamação , Camundongos , PTEN Fosfo-Hidrolase/genética , TreoninaRESUMO
The molecular knowledge of endometrial stromal neoplasms has been rapidly increasing and is considered complementary to morphologic and immunohistochemical findings for better categorization of these tumors. The most common molecular alteration observed in low-grade endometrial stromal sarcomas is the JAZF1-SUZ12 fusion, whereas, low-grade endometrial stromal sarcoma with sex cord-like differentiation have been shown more commonly to have fusions involving PHF1. Herein, we present a low-grade endometrial stromal sarcoma with sex cord-like differentiation with a fluorescence in situ hybridization showing the apparent loss of one copy of JAZF1 5' and 3' signals, rather than the expected "break-apart" pattern seen in the setting of a JAZF1 fusion. The case was then further evaluated by chromosome microarray and RNA fusion analysis. Overall, the molecular findings supported a PHF1-JAZF1 fusion with deletions right before and after the JAZF1 locus, impairing probe binding and resulting in the unusual "deletion" pattern observed in the JAZF1 fluorescence in situ hybridization, which would not intuitively suggest a fusion involving JAZF1. This case illustrates the importance of integration of morphological and molecular findings as well as the limitations of fluorescence in situ hybridization in detecting fusions, particularly in the setting of more complex chromosomal alterations even though the fusion partners are well-known.
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Neoplasias do Endométrio , Tumores do Estroma Endometrial , Sarcoma do Estroma Endometrial , Proteínas Correpressoras/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Tumores do Estroma Endometrial/diagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente , Proteínas do Grupo Polycomb/genética , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/patologia , Fatores de Transcrição/genéticaRESUMO
The microbial colonization of the lower female reproductive tract has been extensively studied over the past few decades. In contrast, the upper female reproductive tract including the uterine cavity and peritoneum where the ovaries and fallopian tubes reside were traditionally assumed to be sterile under non-pathologic conditions. However, recent studies applying next-generation sequencing of the bacterial 16S ribosomal RNA gene have provided convincing evidence for the existence of an upper female reproductive tract microbiome. While the vaginal microbiome and its importance for reproductive health outcomes has been extensively studied, the microbiome of the upper female reproductive tract and its relevance for gynecologic cancers has been less studied and will be the focus of this article. This targeted review summarizes the pertinent literature on the female reproductive tract microbiome in gynecologic malignancies and its anticipated role in future research and clinical applications in personalized medicine.
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There are a number of normal variants and pitfalls which are important to consider when evaluating F-18 Fluorodeoxyglucose (FDG) with Positron Emission Tomography (PET) in breast cancer patients. Although FDG-PET is not indicated for the initial diagnosis of breast cancer, focally increased glucose metabolism within breast tissue represents a high likelihood for a neoplastic process and requires further evaluation. Focally increased glucose metabolism is not unique to breast cancer. Other malignancies such as lymphoma, metastases from solid tumors as well as inflammatory changes also may demonstrate increased glucose metabolism either within the breast or at other sites throughout the body. Importantly, benign breast disease may also exhibit increased glucose metabolism, limiting the specificity of FDG-PET. Breast cancer has a wide range of metabolic activity attributed to tumor heterogeneity and breast cancer subtype. Intracellular signaling pathways regulating tumor glucose utilization contribute to these pitfalls of PET/CT in breast cancer. The evaluation of axillary lymph nodes by FDG-PET is less accurate than sentinel lymph node procedure, however is very accurate in identifying level II and III axillary lymph node metastases or retropectoral metastases. It is important to note that non-malignant inflammation in lymph nodes are often detected by modern PET/CT technology. Therefore, particular consideration should be given to recent vaccinations, particularly to COVID-19, which can commonly result in increased metabolic activity of axillary nodes. Whole body FDG-PET for staging of breast cancer requires specific attention to physiologic variants of FDG distribution and a careful comparison with co-registered anatomical imaging. The most important pitfalls are related to inflammatory changes including sarcoidosis, sarcoid like reactions, and other granulomatous diseases as well as secondary neoplastic processes.
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Neoplasias da Mama/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Mama/patologia , Fluordesoxiglucose F18 , Humanos , Metástase Neoplásica , Estadiamento de NeoplasiasRESUMO
BACKGROUND: We developed a fluorophore-conjugated peptide agent, SBK4, that detects a tumor-specific proteolyzed form of the cell adhesion molecule, PTPmu, found in the tumor microenvironment. We previously demonstrated its tissue specific distribution in high-grade brain tumors. To extend those studies to other aggressive solid tumor types, we assessed the tissue distribution of PTPmu/SBK4 in a set of matched gynecologic cancer patient derived xenografts (PDXs) and primary patient tumors, as well as a limited cohort of tumors from gynecological cancer patients. PDXs isolated from the tissues of cancer patients have been shown to yield experimentally manipulatable models that replicate the clinical characteristics of individual patients' tumors. In this study, gynecological cancer PDXs and patient biopsies were examined to determine if tumor-specific proteolyzed PTPmu was present. METHODS: We used the peptide agent SBK4 conjugated to the fluorophore Texas Red (TR) to label tumor tissue microarrays (TMAs) containing patient and/or PDX samples from several high-grade gynecologic cancer types, and quantified the level of staining with Image J. In one TMA, we were able to directly compare the patient and the matched PDX tissue on the same slide. RESULTS: While normal tissue had very little SBK4-TR staining, both primary tumor tissue and PDXs have higher labeling with SBK4-TR. Matched PDXs and patient samples from high-grade endometrial and ovarian cancers demonstrated higher levels of PTPmu by staining with SBK4 than normal tissue. CONCLUSION: In this sample set, all PDXs and high-grade ovarian cancer samples had increased labeling by SBK4-TR compared with the normal controls. Our results indicate that proteolyzed PTPmu and its novel peptide detection agent, SBK4, allow for the visualization of tumor-specific changes in cell adhesion molecules by tissue-based staining, providing a rationale for further development as an imaging agent in aggressive solid tumors, including gynecological cancers.
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Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.
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Carcinogênese/genética , Transformação Celular Neoplásica/genética , Imunidade Inata/genética , MicroRNAs/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Núcleo Celular/patologia , Transformação Celular Neoplásica/patologia , Citocinese , Dano ao DNA , Células Epiteliais/patologia , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Instabilidade Genômica , Células HEK293 , Humanos , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , MicroRNAs/genética , Mitose , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismoRESUMO
A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer (TNBC), a disease commonly treated with these drugs. Here, we report that LIN9 is further elevated with acquisition of taxane resistance. Inhibiting LIN9 genetically or by suppressing its expression with a global BET inhibitor restored taxane sensitivity by inducing mitotic progression errors and apoptosis. While sustained LIN9 is necessary to maintain taxane resistance, there are no inhibitors that directly repress its function. Hence, we sought to discover a druggable downstream transcriptional target of LIN9. Using a computational approach, we identified NIMA-related kinase 2 (NEK2), a regulator of centrosome separation that is also elevated in taxane-resistant cells. High expression of NEK2 was predictive of low survival rates in patients who had residual disease following treatment with taxanes plus an anthracycline, suggesting a role for this kinase in modulating taxane sensitivity. Like LIN9, genetic or pharmacologic blockade of NEK2 activity in the presence of paclitaxel synergistically induced mitotic abnormalities in nearly 100% of cells and completely restored sensitivity to paclitaxel, in vitro. In addition, suppressing NEK2 activity with two distinct small molecules potentiated taxane response in multiple in vivo models of TNBC, including a patient-derived xenograft, without inducing toxicity. These data demonstrate that the LIN9/NEK2 pathway is a therapeutically targetable mediator of taxane resistance that can be leveraged to improve response to this core chemotherapy. SIGNIFICANCE: Resistance to chemotherapy is a major hurdle for treating patients with cancer. Combining NEK2 inhibitors with taxanes may be a viable approach for improving patient outcomes by enhancing mitotic defects induced by taxanes alone.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Paclitaxel/farmacologia , Taxoides/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Senescência Celular , Centrossomo/enzimologia , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Xenoenxertos , Humanos , Mitose/genética , Quinases Relacionadas a NIMA/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Taxoides/administração & dosagem , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Ensaio Tumoral de Célula-Tronco , Proteínas Supressoras de Tumor/metabolismo , Regulação para CimaRESUMO
Lobular neoplasia (LN), invasive lobular breast cancer (ILBC) and related pleomorphic variants represent a distinct group of neoplastic mammary gland lesions. This study assessed the inter-observer agreement of histological grading in a series of ILBC and LN. 54 cases (36x ILBC, 18x LN) were evaluated by 17 observers. 3978 classification calls on various histological features, including nuclear grade, proliferative activity (Ki67 immunohistochemistry, categorical scoring), histological grade and pleomorphism were obtained. Pairwise Cohen's kappa values were calculated and compared between various features and different observer subsets with variable histomorphological experience. In ILBC, pairwise inter-observer agreement for histological grade ranged from poor to almost perfect concordance and was higher in advanced and experienced histopathologists compared with beginners (P < 0.001). Agreement for proliferation (Ki67) ranged from slight to almost perfect concordance and was also higher in advanced and experienced histopathologists (P < 0.001). Considering different features, agreement for proliferation (Ki67) was superior to agreement for histological grade and nuclear grade, even among advanced and experienced histopathologists (P < 0.001). In LN, agreement for B-classification ranged from poor to almost perfect concordance and was higher in advanced and experienced histopathologists (P < 0.001). Considering different features, agreement for proliferation (Ki67 in LN) was superior to subclassification agreement based on conventional features, such as acinar distention and nuclear grade (P < 0.001). In summary, pairwise inter-observer concordance of histological grading of ILBC and LN is dependent on histomorphological experience. Assessment of proliferation by Ki67 immunohistochemistry is associated with favorable inter-observer agreement and can improve histological grading of ILBC as well as LN.
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Carcinoma de Mama in situ/patologia , Neoplasias da Mama/patologia , Carcinoma Lobular/patologia , Gradação de Tumores/métodos , Biomarcadores Tumorais/análise , Carcinoma de Mama in situ/classificação , Neoplasias da Mama/classificação , Carcinoma Lobular/classificação , Feminino , Humanos , Gradação de Tumores/normas , Variações Dependentes do ObservadorRESUMO
OBJECTIVE: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. METHODS: We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). RESULTS: 877 patients were included from published and unpublished studies. Median PFS and OS were 15â¯months (IQR 5-65) and 28â¯months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66; Pâ¯<â¯0·001) and 0·65 (95% CI 0·50-0·85, Pâ¯=â¯0·002) respectively; no heterogeneity was identified (PFS: Qâ¯=â¯6·42, Pâ¯=â¯0·698, I2â¯=â¯0·0%; OS: Qâ¯=â¯6·89, Pâ¯=â¯0·648, I2â¯=â¯0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (nâ¯=â¯80) were more likely to achieve CRS3 (Pâ¯=â¯0·027). CONCLUSIONS: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos , Biomarcadores Tumorais/análise , Intervalo Livre de Doença , Neoplasias das Tubas Uterinas/mortalidade , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Terapia Neoadjuvante , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Resultado do TratamentoRESUMO
Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma-specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type Aα in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo. Furthermore, small molecule-mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo. These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations. SIGNIFICANCE: This study characterizes a highly recurrent, disease-specific PP2A PPP2R1A mutation as a driver of endometrial carcinoma and a target for novel therapeutic development.See related commentary by Haines and Huang, p. 4009.
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Neoplasias do Endométrio , Proteína Fosfatase 2/genética , Carcinogênese , Feminino , Humanos , Mutação , Recidiva Local de NeoplasiaRESUMO
OBJECTIVE: To provide a modern overview for radiologists of the unique radiological, pathological, and clinical features of uterine carcinosarcoma (UCS). RESULTS: UCS is a unique gynecological malignancy that continues to present diagnostic and therapeutic challenges to the field of oncology. The classification and clinical understanding of this malignancy have evolved in recent years, yielding a modern conceptualization of a neoplastic entity that has been well studied but incompletely understood. As UCS causes a significant proportion of deaths secondary to uterine cancer, developing a familiarity with the imaging and clinical features of this entity is critical. In addition to summarizing the modern understanding of this tumor variant, an overview of the common imaging features of UCS will be presented. The role of radiological staging, imaging findings on presentation and follow-up imaging, and modern treatment paradigms will be discussed. Lastly, the current treatment paradigms and surveillance recommendations for UCS will be summarized. CONCLUSION: Knowledge of the modern understanding of uterine carcinosarcoma, including its relevant imaging and clinical features, is critical for radiologists.
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Carcinossarcoma/diagnóstico por imagem , Neoplasias Uterinas/diagnóstico por imagem , Carcinossarcoma/patologia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Uterinas/patologiaRESUMO
Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44-CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44-PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. SIGNIFICANCE: CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44-PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.See related commentary by Rodrigues and Vanharanta, p. 22.This article is highlighted in the In This Issue feature, p. 1.