Fayth L. Miles

Stepping out of the flow: capillary extravasation in cancer metastasis.

In order for cancer cells to successfully colonize a metastatic site, they must detach from the primary tumor using extracellular matrix-degrading proteases, intravasate and survive in the circulation, evade the immune response, and extravasate the vasculature to invade the target tissue parenchyma, where metastatic foci are established. Though many of the steps of metastasis are widely studied, the precise cellular interactions and molecular alterations associated with extravasation are unknown, and further study is needed to elucidate the mechanisms inherent to this process. Studies of leukocytes localized to inflamed tissue during the immune response may be used to elucidate the process of cancer extravasation, since leukocyte diapedesis through the vasculature involves critical adhesive interactions with endothelial cells, and both leukocytes and cancer cells express similar surface receptors capable of binding endothelial adhesion molecules. Thus, leukocyte extravasation during the inflammatory response has provided a model for transendothelial migration (TEM) of cancer cells. Leukocyte extravasation is characterized by a process whereby rolling mediated by cytokine-activated endothelial selectins is followed by firmer adhesions with β1 and β2 integrin subunits to an activated endothelium and subsequent diapedesis, which most likely involves activation of Rho GTPases, regulators of cytoskeletal rearrangements and motility. It is controversial whether such selectin-mediated rolling is necessary for TEM of cancer cells. However, it has been established that similar stable adhesions between tumor and endothelial cells precede cancer cell transmigration through the endothelium. Additionally, there is support for the preferential attachment of tumor cells to the endothelium and, accordingly, site-specific metastasis of cancer cells. Rho GTPases are critical to TEM of cancer cells as well, and some progress has been made in understanding the specific roles of the Rho GTPase family, though much is still unknown. As the mechanisms of cancer TEM are elucidated, new approaches to study and target metastasis may be utilized and developed.

Quantitative Modeling and Analysis of the Transforming Growth Factor β Signaling Pathway

Transforming growth factor beta (TGF-beta) signaling, which regulates multiple cellular processes including proliferation, apoptosis, and differentiation, plays an important but incompletely understood role in normal and cancerous tissues. For instance, although TGF-beta functions as a tumor suppressor in the premalignant stages of tumorigenesis, paradoxically, it also seems to act as a tumor promoter in advanced cancer leading to metastasis. The mechanisms by which TGF-beta elicits such diverse responses during cancer progression are still not entirely clear. As a first step toward understanding TGF-beta signaling quantitatively, we have developed a comprehensive, dynamic model of the canonical TGF-beta pathway via Smad transcription factors. By describing how an extracellular signal of the TGF-beta ligand is sensed by receptors and transmitted into the nucleus through intracellular Smad proteins, the model provides quantitative insight into how TGF-beta-induced responses are modulated and regulated. Subsequent model analysis shows that mechanisms associated with Smad activation by ligand-activated receptor, nuclear complex formation among Smad proteins, and inactivation of ligand-activated Smad (e.g., degradation, dephosphorylation) may be critical for regulating TGF-beta-targeted functional responses. The model was also used to predict dynamic characteristics of the Smad-mediated pathway in abnormal cells, from which we generated four testable hypotheses regarding potential mechanisms by which TGF-betas tumor-suppressive roles may appear to morph into tumor-promotion during cancer progression.

Insidious Changes in Stromal Matrix Fuel Cancer Progression

Reciprocal interactions between tumor and stromal cells propel cancer progression and metastasis. A complete understanding of the complex contributions of the tumor stroma to cancer progression necessitates a careful examination of the extracellular matrix (ECM), which is largely synthesized and modulated by cancer-associated fibroblasts. This structurally supportive meshwork serves as a signaling scaffold for a myriad of biologic processes and responses favoring tumor progression. The ECM is a repository for growth factors and cytokines that promote tumor growth, proliferation, and metastasis through diverse interactions with soluble and insoluble ECM components. Growth factors activated by proteases are involved in the initiation of cell signaling pathways essential to invasion and survival. Various transmembrane proteins produced by the cancer stroma bind the collagen and fibronectin-rich matrix to induce proliferation, adhesion, and migration of cancer cells, as well as protease activation. Integrins are critical liaisons between tumor cells and the surrounding stroma, and with their mechano-sensing ability, induce cell signaling pathways associated with contractility and migration. Proteoglycans also bind and interact with various matrix proteins in the tumor microenvironment to promote cancer progression. Together, these components function to mediate cross-talk between tumor cells and fibroblasts ultimately to promote tumor survival and metastasis. These stromal factors, which may be expressed differentially according to cancer stage, have prognostic utility and potential. This review examines changes in the ECM of cancer-associated fibroblasts induced through carcinogenesis, and the impact of these changes on cancer progression. The implication is that cancer progression, even in epithelial cancers, may be based in large part on changes in signaling from cancer-associated stromal cells. These changes may provide early prognostic indicators to further stratify patients during treatment or alter the timing of their follow-up visits and observations. Visual Overview: http://mcr.aacrjournals.org/content/12/3/297/F1.large.jpg. Mol Cancer Res; 12(3); 297–312. ©2014 AACR. Visual Overview

Paracrine Factors Produced by Bone Marrow Stromal Cells Induce Apoptosis and Neuroendocrine Differentiation in Prostate Cancer Cells

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.

Increased TGF‐β1‐mediated suppression of growth and motility in castrate‐resistant prostate cancer cells is consistent with Smad2/3 signaling

Elevated TGF‐β levels are associated with prostate cancer progression. Although TGF‐β is a tumor suppressor for normal epithelial and early‐stage cancer cells, it may act paradoxically as a tumor promoter in more advanced cancers, although its effects are largely cell and context dependent. This study analyzed prostate cancer responses to TGF‐β signaling in an isogenic model of androgen‐sensitive and castration‐resistant prostate cancer cells.

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

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‐β (TGF‐β) family cytokines in cytostasis and bone metastasis, the role of TGF‐β signaling in the context of prostate cancer‐BMSC interactions was investigated.

Associations of red and processed meat with survival among patients with cancers of the upper aerodigestive tract and lung.

The effect of red and processed meats on cancer survival is unclear. We sought to examine the role of total and processed red meat consumption on all-cause mortality among patients with cancers of the upper aerodigestive tract (UADT) and lung, in order to test our hypothesis that red or processed meat was associated with overall mortality in these patients. Using data from a population-based case-control study conducted in Los Angeles County, we conducted a case-only analysis to examine the association of red or processed meat consumption on mortality after 12 years of follow-up, using a diet history questionnaire. Cox regression was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for potential confounders. Of 601 UADT cancer cases and 611 lung cancer cases, there were 248 and 406 deaths, respectively, yielding crude mortality rates of 0.07 and 0.12 deaths per year. Comparing the highest with lowest quartile of red meat consumption, the adjusted HR was 1.64 (95% CI, 1.04-2.57) among UADT cancer cases; for red or processed meat, the adjusted HR was 1.76 (95% CI, 1.10-2.82). A dose-response trend was observed. A weaker association was observed with red meat consumption and overall mortality among lung cancer cases. In conclusion, this case-only analysis demonstrated that increased consumption of red or processed meats was associated with mortality among UADT cancer cases and WAS weakly associated with mortality among lung cancer cases.

Small Animal Models for the Study of Cancer in Bone

Advanced cancers commonly result in metastasis to bone where interactions between the cancer cell and the bone microenvironment produce predominantly osteoblastic or osteolytic lesions. In humans bone metastasis is observed in 60–85% of advanced cancers from tissues as disparate as prostate, breast, kidney, and lung [9]. In animals, however, spontaneous bone metastases are uncommon and investigation of the patterns of bone metastasis mimicking human cancer dissemination is challenging. Experimental models of bone metastasis consist of injections of cancer cells or tissue orthotopically, intracardially, intravenously (via the tail vein), or directly intraosseously into immunocompromised hosts, mostly mice, and, rarely, other small mammals such as dogs and cats.

Abstract 3184: TGF-β1 signaling inhibits proliferation but promotes motility with progression to castrate-resistant prostate cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Transforming growth factor-beta1 (TGF-B1) is a tumor suppressor in normal and early stage prostate cancer (PCa) cells, but exerts pro-tumorigenic effects during progression to metastatic disease, and correlates with poor prognosis. However, the mechanisms whereby TGF-B1 induces pro-metastatic action are uknown. Previously it was reported that the LNCaP cell line was insensitive to TGF-B-mediated growth suppression. Thus we sought to examine the TGF-B1-induced proliferative response of increasingly metastatic, lineage-related LNCaP sublines. Under reduced serum conditions we show that TGF-B1 inhibits cell proliferation profoundly and promotes apoptosis in castrate-insensitive LNCaP sublines, whereas inhibition of cell proliferation is marginal in LNCaP cells. Growth inhibitory effects and apoptosis are mediated by active TGF-B receptors, TBRII and TBRI, and the downstream Smad2/3 effectors. Knock down of TBRII with a dominant negative construct, as well as inhibition of kinase activity abrogrates these effects. Additionally, we show that TGF-B enhances cytoskeletal rearrangements and increases motility on selected extracellular matrices in metastatic LNCaP sublines. TGF-B signaling in castrate-resistant PCa cell lines is more robust than in hormonally sensitive clones and leads to selective activation of cell motilty that influences PCa cell metastatic behavior with potential consequences for bone colonization. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3184.

Erratum to: Association of sugary beverages with survival among patients with cancers of the upper aerodigestive tract (Cancer Causes Control, 10.1007/s10552-016-0792-8)

In the purpose section ‘‘all-cause survival’’ was replaced to ‘‘overall survival.’’ In the results section, ‘‘survival’’ was replaced to ‘‘poorer survival.’’ In the conclusion, ‘‘increase survival’’ was replaced to ‘‘decrease survival.’’ Results ‘‘Increased survival’’ was replaced to ‘‘poorer survival.’’ In the second paragraph, ‘‘survival five years post-diagnosis...’’, ‘‘survival’’ was replaced to ‘‘mortality.’’ In the third paragraph, ‘‘inversely associated with survival’’ was replaced to ‘‘inversely associated with reduced survival.’’ Discussion In first paragraph, ‘‘all-cause’’ was replaced to ‘‘poorer.’’ In the second paragraph, ‘‘survival’’ was replaced to ‘‘poorer survival.’’ The online version of the original article can be found under doi:10.1007/s10552-016-0792-8. & Zuo-Feng Zhang zfzhang@ucla.edu 1 Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, 650 Charles E. Young Dr. South, Los Angeles, CA 90095-1772, USA 2 Departments of Epidemiology and Environmental Health Sciences, School of Public Health, and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA 3 Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA 4 Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA 5 Departments of Preventive Medicine and Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA 6 Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA 7 Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA 123 Cancer Causes Control DOI 10.1007/s10552-016-0809-3