A Novel Humanized Immune Stroma PDX Cancer Model for Therapeutic Studies.

Unlabelled: Standard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To address this, using patient-derived tumor cells, patient derived cancer-associated mesenchymal stem/progenitor cells, and human endothelial cells, we created a Human Stroma-Patient Derived Xenograft (HS-PDX) tumor model.

Endometriosis-Associated Mesenchymal Stem Cells Support Ovarian Clear Cell Carcinoma through Iron Regulation.

Unlabelled: Ovarian clear cell carcinoma (OCCC) is a deadly and treatment-resistant cancer, which arises within the unique microenvironment of endometriosis. In this study, we identified a subset of endometriosis-derived mesenchymal stem cells (enMSC) characterized by loss of CD10 expression that specifically support OCCC growth. RNA sequencing identified alterations in iron export in CD10-negative enMSCs and reciprocal changes in metal transport in cocultured OCCC cells.

Risk of Lobular Neoplasia Upgrade with Synchronous Carcinoma.

Background: Atypical lobular hyperplasia (ALH) and classic lobular carcinoma in situ encompass a spectrum of proliferative lesions known as lobular neoplasia (LN). When imaging-concordant and found in isolation on core needle biopsy (CNB), LN infrequently upgrades to carcinoma on surgical excision, and routine excision is not indicated. Upgrade rates in the setting of synchronous carcinoma are not well studied.

Shifting the Soil: Metformin Treatment Decreases the Protumorigenic Tumor Microenvironment in Epithelial Ovarian Cancer.

Controversy persists regarding metformin's role in cancer therapy. Our recent work suggested metformin acts by impacting the tumor microenvironment (TME), normalizing the epigenetic profile of cancer-associated mesenchymal stem cells (CA-MSC). As CA-MSC can negatively impact tumor immune infiltrates, we evaluated metformin's impact on the human TME, focusing on the interplay of stroma and immune infiltrates.

The fallopian tube, "precursor escape" and narrowing the knowledge gap to the origins of high-grade serous carcinoma.

Most ovarian carcinomas are high-grade serous carcinomas (HGSC) that contain TP53 mutations, present at advanced stage, and eventually become resistant to chemotherapy. The rapid evolution of this disease has been attributed to an origin in the distal fallopian tube, in the form of serous tubal intraepithelial carcinomas (STICs). This has led to a disease model where malignancy develops first in the tube and spreads to the peritoneum or regional lymph nodes.

Clinicopathologic and genetic characteristics of interval colorectal carcinomas favor origin from missed or incompletely excised precursors.

Interval colorectal cancers may arise from missed or incompletely excised precursors or from a unique rapid progression pathway. We compared the clinicopathologic and molecular profiles of interval and matched non-interval colorectal cancer to determine whether interval colorectal cancers harbor any unique genetic characteristics. Fifty one of 982 colorectal cancer (5.

Frontiers in the Pathology and Pathogenesis of Ovarian Cancer: Cancer Precursors and "Precursor Escape".

This article summarizes the pathogenesis of ovarian carcinoma, focusing on the paradox of high-grade serous carcinogenesis. The fallopian tube is the prime site of origin in early serous cancers. Because a subset of serous cancers is associated with early serous proliferations absent intramucosal carcinomas, "precursor escape" is emerging, whereby some advanced cancers trace their roots to early serous proliferations.

Evidence for lineage continuity between early serous proliferations (ESPs) in the Fallopian tube and disseminated high-grade serous carcinomas.

The distal Fallopian tube is a site of origin for many 'ovarian' high-grade serous carcinomas (HGSCs) with intraepithelial carcinomas (STICs) that share identical TP53 mutations with metastatic tumors. TP53 mutation-positive early serous proliferations (ESPs) comprise a spectrum including p53 signatures and serous tubal intraepithelial lesions (STILs) and are not considered malignant; however, ESPs are often the only abnormality found in Fallopian tubes of women with metastatic HGSC. The purpose of this study was to determine if a relationship exists between isolated ESPs and concurrent metastatic HGSCs in the absence of STIC.

Evidence of a Monoclonal Origin for Bilateral Serous Tubal Intraepithelial Neoplasia.

Serous tubal intraepithelial carcinoma (STIC) is found in 10% to 60% of cases of tuboovarian high-grade serous carcinoma (HGSC) and is presumed to be the site of origin, linking many HGSCs to the fallopian tube. Bilateral STIC is present in ∼20% of cases. Because clonal Tp53 mutations are a defining feature of HGSC, including their associated STICs, we analyzed 4 cases of bilateral serous tubal intraepithelial neoplasia (STIN), including STIC and Tp53-mutated serous tubal intraepithelial lesions (STILs), associated with HGSC to determine whether they contained the same or different p53 mutations.

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas.

Inhibitors targeting the (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor ( ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer.

Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status.

Previous studies suggest that abnormal energy balance status may dysregulate intestinal epithelial homeostasis and promote colorectal carcinogenesis, yet little is known about how host energy balance and obesity influence enterocyte differentiation during carcinogenesis. We hypothesized that the association between high body mass index (BMI) and colorectal carcinoma incidence might differ according to tumor histopathologic differentiation status. Using databases of the Nurses' Health Study and Health Professionals Follow-up Study, and duplication-method Cox proportional hazards models, we prospectively examined an association between BMI and the incidence of colorectal carcinoma subtypes classified by differentiation features.

Deciphering the Multifactorial Susceptibility of Mucosal Junction Cells to HPV Infection and Related Carcinogenesis.

Human papillomavirus (HPV)-induced neoplasms have long been considered to originate from viral infection of the basal cell layer of the squamous mucosa. However, this paradigm has been recently undermined by accumulating data supporting the critical role of a discrete population of squamo-columnar (SC) junction cells in the pathogenesis of cervical (pre)cancers. The present review summarizes the current knowledge on junctional cells, discusses their high vulnerability to HPV infection, and stresses the potential clinical/translational value of the novel dualistic model of HPV-related carcinogenesis.

Integration of pharmacology, molecular pathology, and population data science to support precision gastrointestinal oncology.

Precision medicine has a goal of customizing disease prevention and treatment strategies. Under the precision medicine paradigm, each patient has unique pathologic processes resulting from cellular genomic, epigenomic, proteomic, and metabolomic alterations, which are influenced by pharmacological, environmental, microbial, dietary, and lifestyle factors. Hence, to realize the promise of precision medicine, multi-level research methods that can comprehensively analyze many of these variables are needed.

Lymphatic injury and regeneration in cardiac allografts.

Background: Severed donor heart lymphatics are not anastomosed to recipient lymphatics in cardiac transplantation. We evaluated the effects of cellular infiltrates of T cells and macrophages on the morphology of lymphatics in heart grafts.

Methods: Dark agouti hearts were transplanted to Lewis or control dark agouti rats on subtherapeutic doses of cyclosporin.