The comparative biology of skeletal metastasis

Bone metastasis, a very common sequelae of cancer, is often associated with great morbidity. Understanding the biology of bone metastases may lead to therapeutic interventions to target the metastases. In addition to replacing bone marrow elements, the presence of tumour cells in bone modulates the normal bone remodelling process. Some tumours result in primarily osteolytic bone lesions, whereas others are associated with osteoblastic bone lesions. In either case, the resulting changes in the bone structure result in weakened bone that induces pain and is predisposed to fracture. The mechanisms through which cancer cells modulate bone remodelling are not clearly defined, but ongoing research using a variety of animal models will hopefully provide clues to prevent or slow the progress of bone metastases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73390/1/j.1476-5829.2003.00023.x.pd

Immune mediators in the tumor microenvironment of prostate cancer

Prostate cancer tissue is composed of both cancer cells and host cells. The milieu of host components that compose the tumor is termed the tumor microenvironment (TME). Host cells can be those derived from the tissue in which the tumor originates (e.g., fibroblasts and endothelial cells) or those recruited, through chemotactic or other factors, to the tumor (e.g., circulating immune cells). Some immune cells are key players in the TME and represent a large proportion of non‐tumor cells found within the tumor. Immune cells can have both anti‐tumor and pro‐tumor activity. In addition, crosstalk between prostate cancer cells and immune cells affects immune cell functions. In this review, we focus on immune cells and cytokines that contribute to tumor progression. We discuss T‐regulatory and T helper 17 cells and macrophages as key modulators in prostate cancer progression. In addition, we discuss the roles of interleukin‐6 and receptor activator of nuclear factor kappa‐B ligand in modulating prostate cancer progression. This review highlights the concept that immune cells and cytokines offer a potentially promising target for prostate cancer therapy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152631/1/cac2s4088001701983.pd

Targeted Notch1 inhibition with a Notch1 antibody, OMP-A2G1, decreases tumor growth in two murine models of prostate cancer in association with differing patterns of DNA damage response gene expression

Notch plays a protumorigenic role in many cancers including prostate cancer (PCa). Global notch inhibition of multiple Notch family members using γ-secretase inhibitors has shown efficacy in suppressing PCa growth in murine models. However, global Notch inhibition is associated with marked toxicity due to the widespread function of many different Notch family members in normal cell physiology. Accordingly, in the current study, we explored if specific inhibition of Notch1 would effectively inhibit PCa growth in a murine model. The androgen-dependent VCaP and androgen-independent DU145 cell lines were injected subcutaneously into mice. The mice were treated with either control antibody 1B7.11, anti-Notch1 antibody (OMP-A2G1), docetaxel or the combination of OMP-A2G1 and docetaxel. Tumor growth was measured using calipers. At the end of the study, tumors were assessed for proliferative response, apoptotic response, Notch target gene expression, and DNA damage response (DDR) expression. OMP-A2G1 alone inhibited tumor growth of both PCa cell lines to a greater extent than docetaxel alone. There was no additive or synergistic effect of OMP-A2G1 and docetaxel. The primary toxicity was weight loss that was controlled with dietary supplementation. Proliferation and apoptosis were affected differentially in the two cell lines. OMP-A2G1 increased expression of the DDR gene GADD45α in VCaP cells but downregulated GADD45α in Du145 cells. Taken together, these data show that Notch1 inhibition decreases PCa xenograft growth but does so through different mechanisms in the androgen-dependent VCaP cell line vs the androgen-independent DU145 cell line. These results provide a rationale for further exploration of targeted Notch inhibition for therapy of PCa.We examined whether specific inhibition of Notch1, as opposed to global inhibition of multiple Notch molecules, would effectively inhibit PCa growth in a murine model. We showed that anti-Notch1 (OMP-A2G1) treatment in androgen-dependent VCaP and androgen-independent DU145 xenograft were effective in reducing tumor growth through different mechanisms.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151373/1/jcb28954.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151373/2/jcb28954_am.pd

CCR2 expression correlates with prostate cancer progression

Although the primary role of chemokines and their receptors is controlling the trafficking of leukocytes during inflammatory responses, they also play pleoitropic roles in cancer development. There is emerging evidence that cancer cells produce chemokines that induce tumor cell proliferation or chemotaxis in various cancer types. We have previously reported that MCP-1 acts as a paracrine and autocrine factor for prostate cancer (PCa) growth and invasion. As the cellular effects of MCP-1 are mediated by CC chemokine receptor 2 (CCR2), we hypothesized that CCR2 may contribute PCa progression. Accordingly, we first determined CCR2 mRNA and protein expression in various cancer cell lines, including PCa and other cancer types. All cells expressed CCR2 mRNA and protein, but in PCa, more aggressive cancer cells such as C4-2B, DU145, and PC3 expressed a higher amount of CCR2 compared with the less aggressive cancer cells such as LNCaP or non-neoplastic PrEC and RWPE-1 cells. Further, we found a positive correlation between CCR2 expression and PCa progression by analyzing an ONCOMINE gene array database. We confirmed that CCR2 mRNA was highly expressed in PCa metastatic tissues compared with the localized PCa or benign prostate tissues by real-time RT-PCR. Finally, CCR2 protein expression was examined by immunohistochemical staining on tissue microarray specimens from 96 PCa patients and 31 benign tissue controls. We found that CCR2 expression correlated with Gleason score and clinical pathologic stages, whereas lower levels of CCR2 were expressed in normal prostate tissues. These results suggest that CCR2 may contribute to PCa development. J. Cell. Biochem. 101: 676–685, 2007. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56008/1/21220_ftp.pd

Wnt3a: functions and implications in cancer

Abstract Wnt3a, one of Wnt family members, plays key roles in regulating pleiotropic cellular functions, including self-renewal, proliferation, differentiation, and motility. Accumulating evidence has suggested that Wnt3a promotes or suppresses tumor progression via the canonical Wnt signaling pathway depending on cancer type. In addition, the roles of Wnt3a signaling can be inhibited by multiple proteins or chemicals. Herein, we summarize the latest findings on Wnt3a as an important therapeutic target in cancer.http://deepblue.lib.umich.edu/bitstream/2027.42/113235/1/40880_2015_Article_52.pd

Carnitine and Dehydroepiandrosterone Sulfate Induce Protein Synthesis in Porcine Primary Osteoblast-Like Cells

Age-related bone loss eventually leads to osteopenia in men and women. The etiology of age-related bone loss is currently unknown; however, decreased osteoblast activity contributes to this phenomenon. In turn, osteoblast proliferation and function is dependent on energy production, thus the loss of energy production that occurs with age may account for the deficient osteoblast activity. Carnitine and dehydroepiandrosterone-sulfate (DHEAS), both of which decline with age, promote energy production through fatty acid metabolism. Thus, we hypothesized that carnitine and DHEAS would increase osteoblast activity in vitro . Accordingly, we measured the effect of carnitine and DHEAS on palmitic acid oxidation as a measure of energy production, and alkaline phosphatase (ALP) activity and collagen type I (COL) as indices of osteoblast function in primary porcine osteoblast-like cell cultures. Carnitine (10 −3 and 10 −1 M) but not DHEAS (10 −9 , 10 −8 , and 10 −7 M) increased carnitine levels within the cells. Carnitine alone and in combination with DHEAS increased palmitic acid oxidation. Both carnitine and DHEAS alone and in an additive fashion increased ALP activity and COL levels. These results demonstrate that in osteoblast-like cells in vitro, energy production can be increased by carnitine and osteoblast protein production can be increased by both carnitine and DHEAS. These data suggest that carnitine and DHEAS supplementation in the elderly may stimulate osteoblast activity and decrease age-related bone loss.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42359/1/223-64-6-527_64n6p527.pd

Metformin targets multiple signaling pathways in cancer

Abstract Metformin, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 diabetes, has become the focus of intense research as a candidate anticancer agent. Here, we discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addition, cutting-edge targeting of cancer stem cells by metformin is summarized.http://deepblue.lib.umich.edu/bitstream/2027.42/135949/1/40880_2017_Article_184.pd

Providing prostate cancer survivorship care in Japan: Implications from the USA care model

Despite an increasing number of prostate cancer survivors in Japan, the current delivery of prostate cancer survivorship care is insufficient and lacks a multidisciplinary approach. We carried out a study to characterize prostate cancer survivorship care in Japan, examine the Japanese workforce available to deliver survivorship care, introduce a conceptual framework for survivorship and identify opportunities to improve Japanese survivorship care. We systematically searched PubMed for prostate cancer survivorship care studies, including those from Japan. We also searched the internet for prostate cancer guidelines relevant to survivorship care. We found 392 articles, of which 71 were relevant, read in detail and reported here. In Japan, survivorship care is mostly provided by urologists. Primary care as a specialty does not exist in Japan, and there are no independent nurse practitioners or physician assistants to assist with survivorship care. Japanese quality of life studies characterize the long‐term effects of prostate cancer treatment, but routine use of patient‐reported outcomes is not common in Japan. In the USA, in light of a growing comprehensive awareness of challenges facing survivors and their providers, the American Cancer Society prostate cancer survivorship care guidelines serve as a tool for optimizing the management of long‐term treatment effects and coordination of care. In order to deliver high‐quality survivorship care in Japan, urologists need to establish collaborations with other disciplines within the delivery system. A multidisciplinary guideline for prostate cancer survivorship care in Japan appears warranted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134455/1/iju13186_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134455/2/iju13186.pd