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.

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.

TGF-β 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.

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.