Inclusion of the US Preventive Services Task Force Recommendation for Mammography in State Comprehensive Cancer Control Plans in the US.

Importance: The recommendations for the age and frequency that women at average risk for breast cancer should undergo breast cancer mammography screening have been a matter of emotional, political, and scientific debate over the past decades. Multiple national organizations provide recommendations for breast cancer screening age and frequency. US Centers for Disease Control and Prevention (CDC) funding for state comprehensive cancer control (CCC) planning requires compliance with stated objectives for attaining goals. US Preventive Services Task Force (USPSTF) recommendations on cancer prevention and control are currently used to require coverage of prevention services. Objectives: To evaluate the consistency of state CCC plan objectives compared with the most current (2016) USPSTF recommendations for the age and frequency that individuals should undergo mammography screening and to make recommendations for improvement of state CCC plans. Design, Setting, and Participants: This cross-sectional study used a descriptive, point-in-time evaluation and was conducted from November 1, 2019, to June 30, 2021. In November 2019, the most recent CCC plans from 50 US states and the District of Columbia were downloaded from the CDC website. The recommended ages at which to begin and end mammography examinations and the frequency of mammography examinations were extracted from plan objectives. Main Outcomes and Measures: The recommendations found in CCC plan objectives regarding the ages at which to begin and end mammography examinations and the frequency of mammography examinations for women with average risk for breast cancer were compared with USPSTF recommendations. Results: Of the 51 CCC plans, 16 (31%) were consistent with all USPSTF recommendations for age and frequency that women at average risk should undergo mammography. Twenty-six plans (51%) were partially consistent with recommendations, and 9 plans (18%) were not consistent with any of the 3 guideline components. Conclusions and Relevance: Compared with the USPSTF recommendation, state CCC plans are not homogenous regarding the age and frequency that women at average risk for breast cancer should undergo mammography. This variation is partially due to differences in state-specific planning considerations and discretion, variations in recommendations among national organizations, and publication of plans prior to the most current USPSTF recommendation (2016). Specifying the concept that high-risk populations need different age and frequency of screening recommendations than the general population may reduce heterogeneity among plans.

Inclusion of Evidence-Based Breast Cancer Control Recommendations and Guidelines in State Comprehensive Cancer Control Plans.

INTRODUCTION: Each US state, territory, and tribe/tribal organization is supported by the Centers for Disease Control and Prevention to develop and implement a comprehensive cancer control (CCC) plan. The objective of this study was to inform areas for improvement of those plans. METHODS: To show how CCC plans can be improved, we used the example of breast cancer, which has a long public health history and an established, broad spectrum of prevention and control activities. We evaluated the inclusion of evidence-based breast cancer prevention topics as provided by guidelines from the Centers for Disease Control and Prevention (CDC) and recommendations of the US Preventive Services Task Force (USPSTF) in each state's CCC plan. From January through March 2019, we downloaded CCC plans from each state and the District of Columbia and abstracted and quantified the content of plans for 1) discussion of data on breast cancer mortality, breast cancer incidence, uptake of mammography; 2) statement of objective to reduce the burden of breast cancer; and 3) review of CDC guidelines and USPSTF recommendations. RESULTS: The discussion of breast cancer-relevant topics and specification of objectives was incomplete. Of 51 plans, data on breast cancer mortality and incidence and uptake of mammography were reported in 53% (n = 27) to 76% (n = 39) of plans. CDC and USPSTF recommendations for breast cancer-specific interventions were discussed in only 6% (n = 3) to 37% (n = 19) of plans. Discussion of general cancer prevention topics relevant to breast cancer ranged from 10% (n = 5) to 61% (n = 31) of plans. CONCLUSION: Our findings inform areas for quality improvement of state CCC plans and may contribute to other areas of public health planning.

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma.

Inhibition of the major lysosomal proteases, cathepsins B, D, and L, impairs growth of several cell types but leads to apoptosis in neuroblastoma. The goal of this study was to examine the mechanisms by which enzyme inhibition could cause cell death. Cathepsin inhibition caused cellular accumulation of fragments of the insulin growth factor 1 (IGF-1) receptor. The fragments were located in dense organelles that were characterized as autophagosomes. This novel discovery provides the first clear link between lysosomal function, autophagy, and IGF-1- mediated cell proliferation. A more in-depth analysis of the IGF1 signaling pathway revealed that the mitogen-activated protein kinase (MAPK) cell-proliferation pathway was impaired in inhibitor treated cells, whereas the Akt cell survival pathway remained functional. Shc, an adapter protein that transmits IGF-1 signaling through the MAPK pathway, was sequestered in autophagosomes; whereas IRS-2, an adapter protein that transmits IGF-1 signaling through the Akt pathway, was unaffected by cathepsin inhibition. Furthermore, Shc was sequestered in autophagosomes as its active form, indicating that autophagy is a key mechanism for downregulating IGF-1-induced cell proliferation. Cathepsin inhibition had a greater effect on autophagic sequestration of the neuronal specific adapter protein, Shc-C, than ubiquitously expressed Shc-A, providing mechanistic support for the enhanced sensitivity of neuronally derived tumor cells. We also observed impaired activation of MAPK by epidermal growth factor treatment in inhibitor-treated cells. The Shc adapter proteins are central to transducing proliferation signaling by a range of receptor tyrosine kinases; consequently, cathepsin inhibition may become an important therapeutic approach for treating neuroblastoma and other tumors of neuronal origin.

Transforming growth factor-ß signaling induced during prostate cancer cell death and neuroendocrine differentiation is mediated by bone marrow stromal cells.

INTRODUCTION: Prostate cancer that has metastasized to bone undergoes critical interactions with bone marrow stromal cells (BMSCs), ultimately promoting tumor survival. Previous studies have shown that BMSCs secrete factors that promote prostate cancer apoptosis or neuroendocrine differentiation. Because of the significance of transforming growth factor-ß (TGF-ß) family cytokines in cytostasis and bone metastasis, the role of TGF-ß signaling in the context of prostate cancer-BMSC interactions was investigated. METHODS: The role of TGF-ß family signaling in BMSC-induced apoptosis of lineage-related prostate cancer cells was investigated in live/dead assays. SMAD phosphorylation or activity during apoptosis and neuroendocrine differentiation was investigated using immunofluorescence, Western blotting, and luciferase reporter assays, along with the ALK-4, -5, -7 kinase inhibitor, SB-431542. RESULTS: Treatment of castration-resistant prostate cancer cells with SB-431542 resulted in significant reduction of apoptosis mediated by HS-5 BMSCs, supporting the involvement of TGF-ß/SMAD signaling during this event. Interestingly, however, pre-treatment of BMSCs with TGF-ß1 (5 ng/mL) yielded a conditioned medium that elicited a marked reduction in prostate cancer death. Phosphorylated-SMAD2 (P-SMAD2) was activated in BMSC-triggered transdifferentiated prostate cancer cells, as demonstrated through immunoblotting and luciferase reporter assays. However, SB-431542 did not restore androgen receptor and prostate specific antigen levels down-regulated by BMSC-secreted factors. Prostate cancer cells induced to undergo neuroendocrine differentiation in a BMSC-independent mechanism also showed elevated levels of P-SMAD2. DISCUSSION: Collectively, our findings indicate that: (1) TGF-ß family cytokines or regulated factors secreted from BMSCs are involved in prostate cancer apoptosis; (2) TGF-ß signaling in prostate cancer cells is induced during neuroendocrine differentiation; and (3) TGF-ß1 stimulation of BMSCs alters paracrine signaling to create a permissive environment for prostate cancer survival, suggesting a mechanism for prostate cancer-mediated colonization of bone. CONCLUSIONS: TGF-ß signaling resulting in activation of SMAD2 in prostate cancer may be an indicator of cellular stress in the presence of toxic paracrine factors released from the bone marrow stroma, ultimately fostering prostate cancer colonization of bone.

Paracrine factors produced by bone marrow stromal cells induce apoptosis and neuroendocrine differentiation in prostate cancer cells.

BACKGROUND: Preferential bony metastasis of human prostate cancer (PCa) cells contributes to disease mortality and morbidity. Local factors in bone stromal extracellular matrix microenvironment affect tumor growth through paracrine interactions between tumor and stromal cells. METHODS: Using co-culture and medium transfer, we used several methods to assess interactions between PCa and bone stromal cells using three PCa cell lines: PC3, LNCaP, and the LNCaP derivative, C4-2B. RESULTS: Co-culture of LNCaP and C4-2B cells with bone marrow stromal cell lines, HS27a and HS5, decreased cell number, as did culture with conditioned medium (CM) harvested from these two cell lines suggesting a soluble paracrine factor was responsible. PC3 cell growth was unaffected. CM harvested from bone stromal cell lines triggered apoptosis in LNCaP and C4-2B cell lines, but not in PC3 cells. Surviving C4-2B cells grown in bone stromal cell CM over several days were growth arrested, suggesting presence of a growth inhibitor. Apoptosis induced by CM was dose-dependent. Flow cytometry demonstrated that over a 5-day culture period in stromal cell CM, LNCaP, and C4-2B cell lines, but not PC3 cells, underwent greater apoptosis than parallel cultures in SF medium. The LNCaP and C4-2B cells showed morphology and biomarker expression consistent with transdifferentiation towards a neuroendocrine phenotype after exposure to stromal cell CM. CONCLUSIONS: The reactive bone stromal microenvironment initially is hostile to PCa cells producing widespread apoptosis. Activation of transdifferentiation in a subset of apoptotic resistant cells may support phenotypic adaptation during disease progression in bone, eventually favoring lethal disease.