Epithelial-mesenchymal transition (EMT) has been implicated as the critical event initiating cancer invasion and metastasis. After disseminating through the circulation, the malignant cells have been proposed to undergo subsequent mesenchymalepithelial transition (MET) to form secondary tumors. However, strong evidence from human tumor specimens for this paradigm is lacking. In carcinomas, cancers derived from epithelial tissues, epithelial morphology and gene expression are always retained to some degree. While mesenchymal transdifferentiation may be involved in the pathogenesis of carcinosarcomas, even in these neoplasms, as well as in germ cell tumors capable of multilineage differentiation, the mesenchymal phenotype does not facilitate metastatic progression. Indeed, most cancers invade and travel through lymphatic and blood vessels via cohesive epithelial migration, rather than going through the EMT-MET sequence. EMT gene expression is also consistently associated with high histologic grade and while the transcription factors, Snail, Slug and Twist have traditionally been thought of as inducers of EMT, under certain conditions, they also mediate dedifferentiation and maintenance of the stem cell state. In various malignancies, including basal-like breast cancer and colorectal cancer, the genetically unstable, undifferentiated phenotype predicts early metastatic spread and poor prognosis. This article discusses some of the controversies surrounding differentiation and metastasis from a clinicopathologic perspective and presents evidence that the epithelial phenotype is maintained throughout the process of cancer metastasis.Metastasis is the main cause of death in cancer patients and is widely claimed to be driven by epithelial-mesenchymal transition (EMT). While the role of EMT in cancer progression has been challenged several years ago, 1 there have nevertheless been numerous studies conducted based on this underlying premise. This article reviews recent developments in the field, as well as presenting the argument that for most cancers, mesenchymal differentiation is not essential for invasion and metastasis. EMT and MetastasisDefinitions of EMT are loose. It is generally agreed that during EMT, epithelial cells show loss of cell-cell adhesion by losing E-cadherin expression, reorganization of the cytoskeleton via switching from keratin to vimentin intermediate filaments, loss of apical-basal polarity, acquisition of a fibroblast-like (i.e., spindle) cell shape and increased motility.
Uterine carcinosarcoma is a clinically aggressive malignancy composed of a mix of carcinomatous and sarcomatous elements. We performed targeted next‐generation sequencing of 27 uterine cancer and sarcoma genes together with immunohistochemical analyses of selected proteins in 30 uterine carcinosarcomas. This included 13 cases in which the distinct carcinoma and sarcoma components were sequenced separately and 10 cases where the metastatic tumours were analysed in addition to the primary tumours. We identified non‐synonymous somatic mutations in 90% of the cases, with 27 of 30 cases (90%) harbouring TP53 alterations. The PI3K pathway was the most commonly mutated signalling pathway with mutations identified in PIK3CA, PTEN, PIK3R1, and/or PIK3R2 in two‐thirds of the cases. Mutations in FBXW7, PPP2R1A, ARID1A and KRAS were demonstrated in a minority of cases. In cases where the carcinomatous and sarcomatous components were separately analysed, most of the mutations identified were present in both components, indicating a common origin for the two components. Furthermore, the same TP53 alterations and/or PI3K pathway mutations seen in the primary tumours were also identified in the metastatic sites. Overall, carcinosarcomas exhibited heterogeneous molecular features that resemble the heterogeneity seen in endometrial carcinomas, with some showing endometrioid carcinoma‐like and others showing serous carcinoma‐like mutation profiles. While patients with serous‐like tumours presented more frequently with advanced‐stage disease compared to patients with endometrioid‐like tumours, there was no statistical difference in outcome between the two groups. Our results provide insights into the oncogenesis of uterine carcinosarcoma and identify targetable mutations that represent early oncogenic events. The findings of the different molecular types of uterine carcinosarcoma that parallel the different molecular types in endometrial carcinoma may have future treatment implications with targeted therapies.
Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy. Experimental Design: Isogenic ARID1A À/À and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A À/À tumors. Results: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for recruitment of 53BP1 and RIF1, key mediators of nonhomologous end-joining (NHEJ) machinery, to DNA lesions. The inability of ARID1A À/À cells to mount NHEJ repair results in a partial cytotoxic response to radiation. Small-molecule compound screens revealed that PARP inhibitors act synergistically with radiation to potentiate cytotoxicity in ARID1A À/À cells. Combination treatment with low-dose radiation and olaparib greatly improved antitumor efficacy, resulting in long-term remission in mice bearing ARID1Adeficient tumors. Conclusions: ARID1A-deficient cells acquire high sensitivity to PARP inhibition after exposure to exogenously induced DNA breaks such as ionizing radiation. Our findings suggest a novel biologically informed strategy for treating ARID1Adeficient malignancies.
Up-regulated expression of telomerase reverse transcriptase (TERT) and subsequent maintenance of telomere length are essential in tumor development. Recent studies have implicated somatic gain-of-function mutations at the TERT promoter as one of the mechanisms that promote transcriptional activation of TERT; however, it remains unclear whether this genetic abnormality is prevalent in gynecologic neoplasms. We performed mutational analysis in a total of 525 gynecological cancers, and correlated TERT promoter mutations with clinicopathological features. With the exception of ovarian clear cell carcinomas, in which mutations were found in 37 (15.9%) of 233 cases, the majority of gynecologic malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with ovarian clear cell carcinoma. Ovarian clear cell carcinoma cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences (p = 0.0238). TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression (p= 4.4×10−9) and PIK3CA mutation (p= 0.0019) in ovarian clear cell carcinomas. No associations with disease-specific survival were observed for ovarian clear cell carcinoma. The above results, in conjunction with our previous report showing longer telomeres in ovarian clear cell carcinomas relative to other types of ovarian cancer, suggests that aberrations in telomere biology may play an important role in the pathogenesis of ovarian clear cell carcinoma.
Purpose : Anti-PD1/PD-L1 immunotherapy has demonstrated success in the treatment of advanced non-small cell lung cancer (NSCLC). Recently, PD1/PD-L1 blockade also has demonstrated interesting results in small trials of neo-adjuvant treatment in Stage IB-IIIA NSCLC. In addition, several clinical trials using anti-PD1/PD-L1 as an adjuvant or neo-adjuvant treatment in resectable stage NSCLC patients are ongoing. However, few analyses of anti- PD1/PD-L1 immunotherapy related biomarkers in early stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early stage SqCLC, providing data for identifying the potential role for anti-PD1/PD-L1 treatment in early stage SqCLC patients. Experimental Design and Results : A total of 255 early stage SqCLC patient specimens were identified within the Strategic Partnering to Evaluate Cancer Signatures (SPECS) program participating centers. PD-L1 protein expression by IHC was evaluated using the Dako PD-L1 22C3 pharmDx kit on the Dako Link 48 auto-stainer. Tumor Mutation Burden (TMB) was calculated based on data from targeted genome sequencing. The T-effector and IFN-γ gene signature was determined from Affymetrix gene chip data from frozen specimens. The prevalence of PD-L1 expression was 9.8% at a tumor proportion score (TPS) cutoff of ≥ 50%. PD- L1 mRNA and PD-L2 mRNA positively correlated with PD-L1 protein expression on tumor cells (TCs) and tumor-infiltrating immune cells (TIICs). PD-L1 protein expression on TIICs was correlated with the T-effector and IFN-y gene signature (P<0.001), but not with TMB. For tumor cells, all of these biomarkers were independent of each other. And neither PD-L1 protein expression, TMB, or T-effector and IFN-γ gene signatures were independently prognostic for patient outcomes. Conclusions : Evaluation of PD-L1 expression, TMB, and T-effector and IFN-γ gene signatures in the early-stage SqCLC cohort were found to be independent of each other and none were associated with overall survival. Results also support the hypothesis that PD-L1 expression is regulated by an intrinsic mechanism on tumor cells and an adaptive mechanism on immune cells.
Women with Lynch syndrome (LS) are at increased risk for the development of epithelial ovarian cancer (OC). Analogous to previous studies on BRCA1/2 mutation carriers, there is evidence to suggest a histotype-specific association in LS-associated OCs (LS-OC). Whereas the diagnosis of high-grade serous carcinoma is an indication for BRCA1/2 germline testing, in contrast, there are no screening guidelines in place for triaging OC patients for LS testing based on histotype. We performed a centralized pathology review of tumor subtype on 20 germline mutation-confirmed LS-OCs, on the basis of morphologic assessment of hematoxylin and eosin-stained slides, with confirmation by immunohistochemistry when necessary. Results from mismatch-repair immunohistochemistry (MMR-IHC) and microsatellite instability (MSI) phenotype status were documented, and detailed pedigrees were analyzed to determine whether previously proposed clinical criteria would have selected these patients for genetic testing. Review of pathology revealed all LS-OCs to be either pure endometrioid carcinoma (14 cases), mixed carcinoma with an endometrioid component (4 cases), or clear cell carcinoma (2 cases). No high-grade or low-grade serous carcinomas or mucinous carcinomas of intestinal type were identified. Tumor-infiltrating lymphocytes were prominent (≥40 per 10 high-powered fields) in 2 cases only. With the exception of 1 case, all tumors tested for MMR-IHC or MSI had an MMR-deficient phenotype. Within this cohort, 50%, 55%, 65%, and 85% of patients would have been selected for genetic workup by Amsterdam II, revised Bethesda Guidelines, SGO 10% to 25%, and SGO 5% to 10% criteria, respectively, with <60% of index or sentinel cases detected by any of these schemas. To further support a subtype-driven screening strategy, MMR-IHC reflex testing was performed on all consecutive non-serous OCs diagnosed at 1 academic hospital over a 2-year period; MMR deficiency was identified in 10/48 (21%) cases, all with endometrioid or clear cell histology. We conclude that there is a strong association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation. These findings have implications for the role of tumor subtype in screening patients with OC for further genetic testing and support reflex MMR-IHC and/or MSI testing for newly diagnosed cases of endometrioid or clear cell ovarian carcinoma.
In chronic lymphocytic thyroiditis (CLT), the follicular epithelial cells display cytological atypia resembling papillary thyroid carcinoma (PTC), and epidemiological studies have suggested an increased risk of PTC in patients with this condition. While reactive atypia is observed diffusely in CLT-affected thyroid parenchyma, it is not unusual to find microscopic foci morphologically distinct from the surrounding parenchyma, exhibiting more pronounced cytological and architectural atypia. These small atypical lesions, which we term "follicular epithelial dysplasia" (FED), are particularly prominent in cases of severe CLT, yet lack invasive growth, papillary architecture, or intranuclear pseudoinclusions. To gain further insight into their biological significance, we constructed a tissue microarray of 70 cases of CLT, comprised of morphologically normal thyroid, thyroid with reactive atypia, FED, follicular nodular disease (nodular hyperplasia or follicular adenoma), and PTC. Immunohistochemical staining was performed for a marker panel including PTC (HBME-1, cytokeratin 19, galectin-3, and cyclin-D1) as well as TTF-1, thyroglobulin, and p63. Slides were digitally scanned and immunohistochemical staining evaluated using automated image analysis software. FED lesions were positive for TTF-1 and thyroglobulin (50/50, 100 %), though some (13/50, 26 %) also expressed p63. Similar to PTC, strong diffuse staining was observed for HBME-1 (43/50, 86 %), cytokeratin 19 (48/50, 96 %), galectin-3 (20/50, 40 %) and cyclin-D1 (38/50, 76 %). In contrast, normal thyroid, reactive atypia, and follicular nodular disease were negative, or at most, exhibited focal weak staining for HBME-1, cytokeratin 19, and galectin-3. The results of this study demonstrate the presence of atypical microscopic lesions in CLT with an immunohistochemical profile similar to PTC, supporting the concept of a premalignant lesion preceding PTC, arising in the context of severe chronic inflammation.
Context.-In osteosarcoma treated with neoadjuvant chemotherapy the extent of tumor necrosis on resection is considered an indicator of treatment response, and this has been shown to correlate with survival in most but not all studies.Objective.-To identify additional histologic variables of prognostic significance in high-grade osteosarcoma.Design.-Slides of pretreatment biopsy and primary postneoadjuvant chemotherapy resections from 165 patients with high-grade osteosarcoma were reviewed. Univariate (Kaplan-Meier) and multivariate (Cox regression) analyses were performed to identify clinical and histomorphologic attributes associated with overall survival.Results.-Univariate analyses confirmed the prognostic significance of metastatic status on presentation, primary tumor size, anatomic site, and histologic subtype. Additionally, the identification of lymphovascular invasion, 10% or more residual viable tumor, and 10 or more mitoses per 10 high-powered fields assessed in posttreatment resections were associated with poor survival, retaining significance in multivariate analyses. Based on results from multivariate analysis, we developed a prognostic index incorporating primary tumor size and site, and significant histologic features assessed on resection (ie, lymphovascular invasion status, mitotic rate, and extent of viable tumor). This scoring system segregates patients into 3 risk categories with significant differences in overall survival and retained significance in an independent validation set of 42 cases.Conclusions.-The integration of clinical and microscopic features improves prognostication of patients with osteosarcoma.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.