Population characteristics, management, and survival outcomes in muscle-invasive urothelial carcinoma undergoing radical resection: the MINOTAUR study.

PURPOSE: To describe the incidence, management, and survival outcomes of patients with muscle-invasive urothelial carcinoma (MIUC) undergoing radical surgery (RS) in France. METHODS: We relied on a non-interventional real-world retrospective study based on French National Hospitalization Database. Adults with MIUC with a first RS between 2015 and 2020 were selected. Subpopulations of patients with RS performed in 2015 and 2019 (pre-COVID-19) were extracted, according to cancer site: muscle-invasive bladder cancer (MIBC) or upper tract urothelial carcinoma (UTUC). Disease-free and overall survival (DFS, OS - Kaplan-Meier) were assessed on the 2015 subpopulation. RESULTS: Between 2015 and 2020, 21,295 MIUC patients underwent a first RS. Of them, 68.9% had MIBC, 28.9% UTUC, and 2.2% both cancers. Apart from fewer men among UTUC (70.2%) than MIBC patients (90.1%), patients' demographic (mean age ~ 73 years) and clinical characteristics were similar whatever the cancer site or year of first RS. In 2019, RS alone was the most frequent treatment, occurring in 72.3% and 92.6% in MIBC and UTUC, respectively. Between 2015 and 2019, neoadjuvant use rate increased from 13.8% to 22.2% in MIBC, and adjuvant use rate increased from 3.7% to 6.3% in UTUC. Finally, median [95% confidence interval] DFS times were 16.0 [14.0-18.0] and 27.0 [23.0-32.0] months among MIBC and UTUC, respectively. CONCLUSION: Among patients with resected MIUC annually, RS alone remained the main treatment. Neoadjuvant and adjuvant use increased between 2015 and 2019. Nonetheless, MIUC remains of poor prognosis, highlighting an unmet medical need, notably among patients at high risk of recurrence.

Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity.

Tumor-associated myeloid cells have been implicated in regulating many of the "hallmarks of cancer" and thus fostering solid tumor development and metastasis. However, the same innate leukocytes also participate in anti-tumor immunity and restraint of malignant disease. While many factors regulate the propensity of myeloid cells to promote or repress cancerous growths, polarized adaptive immune responses by B and T lymphocytes have been identified as regulators of many aspects of myeloid cell biology by specifically regulating their functional capabilities. Here, we detail the diversity of heterogeneous B and T lymphocyte populations and their impacts on solid tumor development through their abilities to regulate myeloid cell function in solid tumors.

FcRgamma activation regulates inflammation-associated squamous carcinogenesis.

Chronically activated leukocytes recruited to premalignant tissues functionally contribute to cancer development; however, mechanisms underlying pro- versus anti-tumor programming of neoplastic tissues by immune cells remain obscure. Using the K14-HPV16 mouse model of squamous carcinogenesis, we report that B cells and humoral immunity foster cancer development by activating Fcgamma receptors (FcgammaRs) on resident and recruited myeloid cells. Stromal accumulation of autoantibodies in premalignant skin, through their interaction with activating FcgammaRs, regulate recruitment, composition, and bioeffector functions of leukocytes in neoplastic tissue, which in turn promote neoplastic progression and subsequent carcinoma development. These findings support a model in which B cells, humoral immunity, and activating FcgammaRs are required for establishing chronic inflammatory programs that promote de novo carcinogenesis.

CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.

During breast cancer development, increased presence of leukocytes in neoplastic stroma parallels disease progression; however, the functional significance of leukocytes in regulating protumor versus antitumor immunity in the breast remains poorly understood. Utilizing the MMTV-PyMT model of mammary carcinogenesis, we demonstrate that IL-4-expressing CD4(+) T lymphocytes indirectly promote invasion and subsequent metastasis of mammary adenocarcinomas by directly regulating the phenotype and effector function of tumor-associated CD11b(+)Gr1(-)F4/80(+) macrophages that in turn enhance metastasis through activation of epidermal growth factor receptor signaling in malignant mammary epithelial cells. Together, these data indicate that antitumor acquired immune programs can be usurped in protumor microenvironments and instead promote malignancy by engaging cellular components of the innate immune system functionally involved in regulating epithelial cell behavior.

Delineating protease functions during cancer development.

Much progress has been made in understanding how matrix remodeling proteases, including metalloproteinases, serine proteases, and cysteine cathepsins, functionally contribute to cancer development. In addition to modulating extracellular matrix metabolism, proteases provide a significant protumor advantage to developing neoplasms through their ability to modulate bioavailability of growth and proangiogenic factors, regulation of bioactive chemokines and cytokines, and processing of cell-cell and cell-matrix adhesion molecules. Although some proteases directly regulate these events, it is now evident that some proteases indirectly contribute to cancer development by regulating posttranslational activation of latent zymogens that then directly impart regulatory information. Thus, many proteases act in a cascade-like manner and exert their functionality as part of a proteolytic pathway rather than simply functioning individually. Delineating the cascade of enzymatic activities contributing to overall proteolysis during carcinogenesis may identify rate-limiting steps or pathways that can be targeted with anti-cancer therapeutics. This chapter highlights recent insights into the complexity of roles played by pericellular and intracellular proteases by examining mechanistic studies as well as the roles of individual protease gene functions in various organ-specific mouse models of cancer development, with an emphasis on intersecting proteolytic activities that amplify programming of tissues to foster neoplastic development.

A genetic study of the role of the Wnt/beta-catenin signalling in Paneth cell differentiation.

Wnt/beta-catenin signalling plays a key role in the homeostasis of the intestinal epithelium. Whereas its role in the maintenance of the stem cell compartment has been clearly demonstrated, its role in the Paneth cell fate remains unclear. We performed genetic studies to elucidate the functions of the Wnt/beta-catenin pathway in Paneth cell differentiation. We analysed mice with inducible gain-of-function mutations in the Wnt/beta-catenin pathway and mice with a hypomorphic beta-catenin allele that have not been previously described. We demonstrated that acute activation of Wnt/beta-catenin signalling induces de novo specification of Paneth cells in both the small intestine and colon and that colon cancers resulting from Apc mutations expressed many genes involved in Paneth cell differentiation. This suggests a key role for the Wnt/beta-catenin pathway in Paneth cell differentiation. We also showed that a slight decrease in beta-catenin gene dosage induced a major defect in Paneth cell differentiation, but only a modest effect on crypt morphogenesis. Overall, our findings show that a high level of beta-catenin activation is required to determine Paneth cell fate and that fine tuning of beta-catenin signalling is critical for correct Paneth cell lineage.

Identification of the IFITM family as a new molecular marker in human colorectal tumors.

We analyzed the expression profiles of intestinal adenomas from a new murine familial adenomatous polyposis model (Apc(delta14/+)) using suppression subtractive hybridization to identify novel diagnostic markers of colorectal carcinogenesis. We identified 18 candidate genes having increased expression levels in the adenoma. Subsequent Northern blotting, real-time reverse transcription-PCR, and in situ hybridization analysis confirmed their induction in beta-catenin-activated epithelial cells of murine adenomas. We showed that most of the genes also have altered expression levels in human colonic adenomas and carcinomas. We focused on the IFITM genes that encode IFN-inducible transmembrane proteins. Serial analyses of gene expression levels revealed high levels of expression in early and late intestinal neoplasm in both mice and humans. Using a conditional mouse model of Apc inactivation and a human colon carcinoma cell line, we showed that IFITM gene expression is rapidly induced after activation of the beta-catenin signaling. Using a large-scale analysis of human tumors, we showed that IFITM gene expression is significantly up-regulated specifically in colorectal tumors and thus may be a useful diagnostic tool in these tumors.

Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine.

Loss of Apc appears to be one of the major events initiating colorectal cancer. However, the first events responsible for this initiation process are not well defined and the ways in which different epithelial cell types respond to Apc loss are unknown. We used a conditional gene-ablation approach in transgenic mice expressing tamoxifen-dependent Cre recombinase all along the crypt-villus axis to analyze the immediate effects of Apc loss in the small intestinal epithelium, both in the stem-cell compartment and in postmitotic epithelial cells. Within 4 days, Apc loss induced a dramatic enlargement of the crypt compartment associated with intense cell proliferation, apoptosis and impairment of cell migration. This result confirms the gatekeeper role of Apc in the intestinal epithelium in vivo. Although Apc deletion activated beta-catenin signaling in the villi, we observed neither proliferation nor morphological change in this compartment. This highlights the dramatic difference in the responses of immature and differentiated epithelial cells to aberrant beta-catenin signaling. These distinct biological responses were confirmed by molecular analyses, revealing that Myc and cyclin D1, two canonical beta-catenin target genes, were induced in distinct compartments. We also showed that Apc is a crucial determinant of cell fate in the murine intestinal epithelium. Apc loss perturbs differentiation along the enterocyte, goblet and enteroendocrine lineages, and promotes commitment to the Paneth cell lineage through beta-catenin/Tcf4-mediated transcriptional control of specific markers of Paneth cells, the cryptdin/defensin genes.