scholarly journals Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault.

2002 ◽  
pp. 61-73 ◽  
Author(s):  
J T Arnold ◽  
J T Isaacs
Keyword(s):  
Prostate Cancer ◽  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Stromal Cells ◽  
Growth Control ◽  
Death Sentence ◽  
Control Mechanisms ◽  
Androgen Ablation ◽  
Androgen Independent

The acquisition of an androgen-independent phenotype by prostate cancer cells is presently a death sentence for patients. In order to have a realistic chance of changing this outcome, an understanding of what drives the progression to androgen independence is critical. We review here a working hypothesis based on the position that the development of androgen-independent epithelial cells is the result of a series of cellular and molecular events within the whole tissue that culminates in the loss of normal tissue-maintained growth control. This tissue includes the epithelial and stromal cells, the supporting extracellular matrix and circulating hormones. This review discusses the characteristics of these malignant cells, the role of stromal cells involved in growth and the differentiation of epithelial cells, and the role of the extracellular matrix as a mediator of the phenotypes of stromal and epithelial cells. In addition, environmental, neuroendocrine and immune factors that may contribute to disturbance of the fine balance of the epithelial-stromal-extracellular matrix connection are considered. While the goal of many therapeutic approaches to prostate cancer has been androgen ablation or targeting the androgen receptor (AR) of epithelial cells, these therapies become ineffective as the cells progress beyond dependence on androgen for growth control. Twenty years ago Sir David Smithers debated that cancer is the result of loss of tolerance within tissues and the organizational failure of normal growth-control mechanisms. This is precipitated by prolonged or abnormal demands for regeneration or repair, rather than of any inherent disorder peculiar to each of the individual components involved. He wrote "It is not the cell itself that is disorderly, but its relationship with the rest of the tissue". We have gained significantly large amounts of precise data on the effects of androgenic ablation on cancerous prostate cells and on the role of the AR in prostate cancer. The need has come to compile this information towards a perspective of dysregulation of tissue as a whole, and to develop experimental systems to address this broader perspective to find and develop therapies for treatment and prevention.

scholarly journals Testosterone, prolactin, and oncogenic regulation of the prostate gland. A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy!

2018 ◽  
Author(s):  
Leslie C. Costello ◽  
Renty B. Franklin
Keyword(s):  
Prostate Cancer ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Prostate Gland ◽  
Peripheral Zone ◽  
Metabolic Function ◽  
Androgen Ablation ◽  
Prolactin Signaling ◽  
Maintenance Metabolism

Hormone-independent malignancy is a major issue of morbidity and deaths that confronts prostate cancer. Despite decades of research, the oncogenic and hormonal implications in the development and progression of prostate malignancy remain mostly speculative. This is largely due to the absence and/or lack of consideration by contemporary clinicians and biomedical investigators regarding the established implications of the co-regulation of testosterone and prolactin in the development, maintenance, metabolism and functions of the prostate gland. Especially relevant is the major metabolic function of production of high levels of citrate by the peripheral zone acinar epithelial cells. Citrate production, along with growth and proliferation by these cells, is regulated by co-existing testosterone and prolactin signaling pathways; and by the oncogenic down-regulation of ZIP1 transporter/zinc/citrate in the development of malignancy. These relationships had not been considered in the issues of hormonedependent malignancy. This review provides the relevant background that has established the dual role of testosterone and prolactin regulation of the prostate gland; which is essential to address the implications in the oncogenic development and progression of hormone-dependent malignancy. The oncogenic factor along with testosterone-dependent and prolactin-dependent relationships leads to the plausible concept that androgen ablation for the treatment of testosterone-dependent malignancy results in the development of prolactin-dependent malignancy; which is testosterone-independent malignancy. Consequently, both testosterone ablation and prolactin ablation are required to prevent and/or abort terminal hormonedependent prostate cancer.

Developmental aspects of secondary palate formation

Development ◽  
1976 ◽  
Vol 36 (2) ◽  
pp. 225-245
Author(s):  
Robert M. Greene ◽  
Robert M. Pratt
Keyword(s):  
Extracellular Matrix ◽  
Cell Death ◽  
Epithelial Cells ◽  
Cell Surface ◽  
Hydrolytic Enzymes ◽  
Cellular Adhesion ◽  
Control Mechanisms ◽  
Adhesive Interaction ◽  
Secondary Palate

Research on development of the secondary palate has, in the past, dealt primarily with morphological aspects of shelf elevation and fusion. The many factors thought to be involved in palatal elevation, such as fetal neuromuscular activity and growth of the cranial base and mandible, as well as production of extracellular matrix and contractile elements in the palate, are mostly based on gross, light microscopic, morphometric or histochemical observations. Recently, more biochemical procedures have been utilized to describe palatal shelf elevation. Although these studies strongly suggest that palatal extracellular matrix plays a major role in shelf movement, interpretation of these data remains difficult owing to the complexity of tissue interactions involved in craniofacial development. Shelf elevation does not appear to involve a single motive factor, but rather a coordinated interaction of all of the abovementioned developmental events. Further analysis of mechanisms of shelf elevation requires development of new, and refinement of existing, in vitro procedures. A system that enables one to examine shelf elevation in vitro would allow more meaningful analysis of the relative importance of the various components in shelf movement. Much more is known about fusion of the palatal shelves, owing in large part to in vitro studies. Fusion of the apposing shelves, both in vivo and in vitro, is dependent upon adhesion and cell death of the midline epithelial cells. Adhesion between apposing epithelial surfaces appears to involve epithelial cell surface macromolecules. Further analysis of palatal epithelial adhesion should be directed towards characterization of those cell surface components responsible for this adhesive interaction. Midline epithelial cells cease DNA synthesis 24–36 h before shelf elevation and contact, become active in the synthesis of cell surface glycoproteins, and subsequently manifest morphological signs of necrosis. Death of the midline epithelial cells is thought to involve a programmed, lysosomal-mediated autolysis. Information regarding the appearance, distribution and quantitation of epithelial hydrolytic enzymes is needed. The control mechanisms which regulate adhesiveness and cell death in the palatal epithelium are not fully understood. Although palatal epithelial-mesenchymal recombination experiments have demonstrated a close relationship between the underlying mesenchyme and the differentiating epithelium, the molecular mechanism of interaction remains unclear. Recently cyclic nucleotides have been implicated as possible mediators of palatal epithelial differentiation. The developing secondary palate therefore offers a system whereby one can probe a variety of developmental phenomena. Cellular adhesion, programmed cell death and epithelial- mesenchymal interactions are all amenable to both morphological as well as bio- chemical analysis. Although research in the field of secondary palate development has been extensive, there still remain many provocative questions relating to normal development of this structure.

Differential expression of neutral endopeptidase-24.11 (neprilysin) and endothelin-converting enzyme in human prostate cancer cell lines

2002 ◽  
Vol 103 (s2002) ◽  
pp. 314S-317S ◽  
Author(s):  
Badar A. USMANI ◽  
Ben HARDEN ◽  
Norman J. MAITLAND ◽  
Anthony J. TURNER
Keyword(s):  
Prostate Cancer ◽  
Epithelial Cells ◽  
Cell Lines ◽  
Prostate Cancer Cell ◽  
Neutral Endopeptidase ◽  
Prostatic Hyperplasia ◽  
Converting Enzyme ◽  
Prostate Cancer Cell Lines ◽  
Endothelin Converting Enzyme ◽  
Androgen Independent

Neutral endopeptidase-24.11 (neprilysin; NEP/CD10) is a cell surface metallopeptidase expressed by prostatic epithelial cells that degrades various bioactive peptides including endothelin. Endothelin-converting enzyme (ECE), the key enzyme of endothelin biosynthesis, catalyses the final processing step in the pathway. Neuropeptide substrates of NEP, including endothelin, have been implicated in the growth of androgen-independent prostate cancer. We have surveyed the expression of NEP and ECE in a range of prostate cancer cell lines. Western analysis reveals that ECE-1 is expressed abundantly in all the malignant cell lines tested, except for LNCaP. In contrast, LNCaP cells express high levels of NEP, while NEP was not detected in PC-3, DU145 and other metastatic cell lines that were tested. Of the normal immortalized prostate epithelial cell lines, PNT1a shows equivalent amounts of NEP and ECE. PNT2-C2 shows poor NEP expression but an abundance of ECE. P4E6, by comparison, has low levels of both ECE and NEP. These differences in expression may render these cell lines useful in experimental models for future study. Benign prostatic hyperplasia primary epithelial cells express much higher levels of NEP than malignant primary epithelial cells, but neither show ECE expression. On the other hand, surrounding stromal cell populations have detectable ECE levels. An absence of ECE in malignant and benign prostatic hyperplasia cells of primary epithelial origin suggests an important role for stromal interaction and paracrine production of ECE within the host. The upregulation of ECE expression in metastatic cells in culture may be indicative of its role in metastatic progression. A differential profile of ECE and NEP could contribute to an abundance of mitogenic peptides aiding the progression of androgen-independent prostate cancer.

scholarly journals Targeting androgen receptor signaling: a historical perspective

2021 ◽  
Author(s):  
Alastair H Davies ◽  
Amina Zoubeidi
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Historical Perspective ◽  
Death Sentence ◽  
Advanced Stage ◽  
Cancer Disease ◽  
Androgen Receptor Signaling ◽  
Androgen Ablation ◽  
First Case ◽  
Prostate Cancer Therapy

The first case of prostate cancer was identified by histological examination by J. Adams, a surgeon at The London Hospital, in 1853. In his report, Adams noted that the condition was “a very rare disease”. Now, over 150 years later, with increased life expectancy and screening, prostate cancer has become one of the most common cancers in men. In the United Sates alone, nearly 200,000 men are diagnosed with prostate cancer annually and about 33,000 succumb to their disease. Fifty years ago, men were typically diagnosed with prostate cancer in their seventies with disease that had metastasized to the bone and/or soft tissue. Diagnosis at such an advanced stage was a death sentence, with patients dying within two years. The pioneering work of Charles Huggins in the 1940s found that metastatic prostate cancer responds to androgen deprivation therapy (ADT), ushering in the rational use of hormone therapies that have irrevocably changed the course of prostate cancer disease management. Medical castration was the first effective systemic targeted therapy for any cancer and, to this day, androgen ablation remains the mainstay of prostate cancer therapy.

scholarly journals Paracrine interactions between epithelial cells promote colon cancer growth

2020 ◽  
Author(s):  
Guillaume Jacquemin ◽  
Annabelle Wurmser ◽  
Mathilde Huyghe ◽  
Wenjie Sun ◽  
Meghan Perkins ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Critical Role ◽  
Essential Factor ◽  
Transcriptional Responses ◽  
Tumour Formation ◽  
Different Types ◽  
The Impact

AbstractTumours are complex ecosystems composed of different types of cells that communicate and influence each other. While the critical role of stromal cells in affecting tumour growth is well established, the impact of mutant cancer cells on healthy surrounding tissues remains poorly defined. Here, we uncovered a paracrine mechanism by which intestinal cancer cells reactivate foetal and regenerative Yap-associated transcriptional programs in neighbouring wildtype epithelial cells, rendering them adapted to thrive in the tumour context. We identified the glycoprotein Thrombospondin-1 (Thbs1) as the essential factor that mediates non-cell autonomous morphological and transcriptional responses. Importantly, Thbs1 is associated with bad prognosis in several human cancers. This study reveals the Thbs1-YAP axis as the mechanistic link mediating paracrine interactions between epithelial cells, promoting tumour formation and progression.

scholarly journals Key Role of Obesity in Genitourinary Tumors with Emphasis on Urothelial and Prostate Cancers

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1225 ◽  
Author(s):  
Matteo Santoni ◽  
Alessia Cimadamore ◽  
Francesco Massari ◽  
Francesco Piva ◽  
Gaetano Aurilio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Body Mass Index ◽  
Body Mass ◽  
Stromal Cells ◽  
Urothelial Cancer ◽  
Abiraterone Acetate ◽  
Survival Outcome ◽  
Adipose Stromal Cells ◽  
Cellular Pathways

Background: In human populations, a certain amount of data correlate obesity/body mass index (BMI) with urothelial cancer (UC) and prostate cancer (PCa) occurrence, however this is not fully elucidated at all stages of disease. In an attempt to shed light on uncertain areas in such field, in the present review we illustrate the main molecular mechanisms linking obesity and cancer, focusing on the correlation between obesity and tumor risk, disease progression and response to chemo- and immunotherapy in patients with UC and the predictive/prognostic role of obesity in PCa patients treated with the currently available therapeutic approaches. Methods: We did a large-scale literature search on existing scientific websites focusing on keywords “obesity”, “body mass index (BMI)”, “urothelial cancer”, “prostate cancer”, “docetaxel”, “cabazitaxel”, “abiraterone acetate”, “enzalutamide”, and “radium223”. Results: Many adipocytes-induced molecules support tumor proliferation through activation of various cellular pathways. The available evidence in the postoperative setting do the role of BMI in oncological outcomes prediction still not completely clear. Likewise, in metastatic UC patients controversial results link the role of obesity/BMI with clinical outcomes of tumor response to chemotherapy. Adipose stromal cells recruitment, induced by PCa cells, from white adipose tissue to the tumor sites inducing cell invasiveness was associated with poor survival. Conflicting data, although more oriented towards a better survival outcome, resulted in obese patients treated with docetaxel. In PCa cell-lines a certain cabazitaxel chemo resistance adipose stromal cells (ASC)-mediated was demonstrated. In metastatic castration-resistant PCa patients with high BMI (>25 kg/m2) receiving abiraterone acetate there were significant worse survival outcomes, while in enzalutamide patients BMI did not affect survival outcome. In radium 223 patients higher BMI significantly correlated with favorable overall survival. Conclusions: The main focus of this review was to understand the interplay between obesity/BMI and UC/PCa. Several pathogenic cellular pathways exploring the issue are discussed, opening the way to challenging tailored treatments on the basis of BMI. Improving the knowledge of molecular connections between obesity and UC and PCa could favor the development of new therapies likely reducing chemo- and immunotherapy drug resistance.

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