Prostate Cancer Vaccines

Standard systemic treatment of prostate cancer today is comprised of antihormonal and cytostatic agents. Vaccine therapy of prostate cancer is principally attractive because of the presence of tumor-associated antigens such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), and others. Most prostate cancer vaccine trials have demonstrated some activation of the immune system, limited clinical success, and few adverse effects.One strategy to overcome the problem of limited clinical success of vaccine therapies in prostate cancer could be strict patient selection. The clinical course of patients with prostate cancer (even in those with PSA relapse following surgery or radiotherapy with curative intention, or those with metastatic disease) can vary significantly. In patients with organ-confined prostate cancer, the most promising immunotherapeutic approach would be an adjuvant therapy following surgery or radiotherapy. Patients with PSA relapse following surgery or radiotherapy could also benefit from immunotherapy because tumor burden is usually low. However, most patients in prostate cancer vaccine trials had metastatic hormone-refractory prostate cancer (HRPC). High tumor burden correlates with immune escape phenomena. Nevertheless, 2 years ago, it was demonstrated, for the first time, that a tumor vaccine can prolong survival compared with placebo in patients with HRPC. This was demonstrated with the vaccine sipuleucel-T (APC-8015; Provenge), a mixture of cells obtained from the patient's peripheral blood by leukapheresis followed by density centrifugation and exposition. The Biologics License Application for this vaccine was denied by the US FDA in mid 2007, however, because the trial had failed to reach the primary endpoint (prolongation of time to tumor progression). Nevertheless, clinical trials with sipuleucel-T are ongoing, and the approach still looks promising.Another interesting approach is a vaccine made from whole tumor cells: GVAX. This vaccine is presently being studied in phase III trials against, and in combination with, docetaxel. The results from these trials will become available in the near future. Besides the precise definition of the disease status of patients with prostate cancer, combinations of vaccine therapy with radiotherapy, chemotherapy, and/or hormonal therapy are approaches that look promising and deserve further investigation.     

Exploring the Origins of the Normal Prostate and Prostate Cancer Stem Cell

Prostate epithelial stem cells (PSCs) are primed by the urogenital mesenchyme to initiate bud formation and branching morphogenesis, ultimately culminating in a glandular structure composed of luminal, basal and neuroendocrine cells. Identity of this cell has remained elusive however cell populations enriched for cells exhibiting stem cell characteristics express the stem cell markers CD133⁺, α2β1^hi, CD44 and Sca-1 along with embryonic stem cell factors including Oct-1, Nanog, Sox2 and nestin. Androgens are critical to prostate organogenesis and play a major role in normal prostate function and the development of prostate cancer. Cell lineage is another variable in the development of prostate cancer. This review discusses the embryonic prostate stem cell niche, normal prostate development, isolation and characterization of normal prostate and prostate cancer stem cells, and current concepts on the origin of prostate cancer. Funding for this work was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK60957) and the Frances Williams Preston Laboratories of the T.J. Martell Foundation. An erratum to this article can be found at     

High-grade Prostatic Intraepithelial Neoplasia of the Prostate: The Precursor Lesion of Prostate Cancer

High-grade intraepithelial neoplasia (HGPIN) is a lesion which is widely believed to be a precursor of prostatic adenocarcinoma. Correct morphologic identification of HGPIN and an understanding of how this diagnosis affects clinical management in the research setting are necessary as HGPIN is a premalignant lesion with many genetic alterations similar to prostate cancer, but is not yet invasive cancer. As such it is critical to differentiate between benign entities, HGPIN, and prostatic adenocarcinoma for experimental design and data interpretation. This review discusses HGPIN, clarifies the terminology used in pathology reports, and describes the clinical and research implications of this entity.     

Wounds That Will Not Heal: Pervasive Cellular Reprogramming in Cancer

There has been an explosion of articles on epithelial-mesenchymal transition and other modes of cellular reprogramming that influence the tumor microenvironment. Many controversies exist and remain to be resolved. The interest of the pathologists in the molecular and functional parallels between wound healing and the developing tumor stroma has its earliest origin in the writings of Rudolph Virchow in the 19^th century. Since then, most of the focus has been primarily on the dynamics of the extracellular matrix; however, new interest has been redirected toward deciphering and understanding the enigmatic, yet elegant, plasticity of the cellular components of the proliferating epithelia and stroma and how they are reciprocally influenced. Citing several examples from breast cancer research, we will trace how these perspectives have unfolded in the pages of The American Journal of Pathology and other investigative journals during the past century, their impact, and where the field is headed.In 1858, Rudolph Virchow first proposed his irritation theory for cancer.^1,2 This concept was based on the observation that neoplastic lesions often develop at sites of chronic irritation. Virchow concluded that irritation of any type, including mechanical, chemical, or thermal, was “the essential factor of neoplastic tissue proliferation.”^{2,pp 511} Through an astute synthesis of these general observations with the microscopic finding that foci of irritation or abnormal excitation were invariably associated with a reactive process characterized by infiltration of inflammatory cells, Virchow later proposed his more celebrated concept that there is a causal link between inflammation and cancer.^1,2 More than a century later, Dvorak colorfully coined the phrase that cancer was “a wound that does not heal,”³ implying that the cellular and biochemical processes associated with wound healing are similar to those involved in the growth and development of tumor stroma. However, one of the earliest written recognitions of this similarity appeared, in 1924, in the Journal of Medical Research, the immediate predecessor of The American Journal of Pathology, in an article submitted by Montrose T. Burrows, entitled “Studies on Wound Healing: I ‘First Intention’ Healing of Open Wounds and the Nature of the Growth Stimulus in the Wound and Cancer.” Although, unlike Virchow, Burrows dismissed the possible significance of the role played by the infiltrating lymphocytes, he did recognize the critical importance of the relationship between the different fixed cells of epithelium and connective tissue in the generation of growth stimuli during the wound response. This led him to suggest that “cancer may be nothing more than a break in the balance” between these two populations. This notion was later reiterated by Haddow⁴ in 1972. Notwithstanding its noted resemblance to cancer growth and invasion, the regenerative processes associated with wound healing have been a favorite topic of investigation by experimental pathologists for more than a century.^5,6 A consistent and recurrent theme has been that the healing wound response can be characterized by three important factors: epithelial movements, cell proliferation, and contraction (or remodeling).^5,7 It is generally accepted that wound healing is a sequential process that can be separated into three overlapping phases in which the appearance, growth, and differentiation of specific constituents have many similarities to developing tumor stroma. They include the following: i) inflammation, ii) proliferation, and iii) maturation. These processes differ in cancer and wound healing at the level of regulation, where there is lost control of multiple cellular, molecular, and biochemical processes that characterize each step.     

Cancer of the Prostate in Blacks

The exact etiology of adenocarcinoma of the prostate gland remains an enigma. However, there appears to be a clear-cut mandate to search for, and to eradicate if possible, all infections of the genital tract including prostatitis. Diets with adequate zinc or zinc supplements should be considered. Sexual practices could be more closely scrutinized. Finally, an urgent appeal is made for intense investigation of this malady.     

Coping with Prostate Cancer: A Meta-Analytic Review

The present meta-analytic review assessed the relations between coping categories and indices of adjustment in men with prostate cancer. Relevant methodological and statistical information was extracted from 33 target studies (n = 3,133 men with prostate cancer). Men with prostate cancer who used approach, problem-focused, and emotion-focused coping were healthier both psychologically and physically, although the effect sizes for problem-focused coping and emotion-focused coping were more modest. For approach coping these effect sizes were particularly strong for measures of self-esteem, positive affect, depression, and anxiety. Conversely, men with prostate cancer who used avoidance coping experienced heightened negative psychological adjustment and physical health, and particularly for measures of positive mood and physical functioning. The findings of this study suggest that active approaches to coping with prostate cancer are beneficial psychologically, physically, and are positively associated with a return to pre-cancer activities.     

前列腺特异抗原及其密度测定在前列腺癌

为探讨前列腺特异抗原（PSA）及前列腺特异抗原密度（PSAD）的临床应用价值,用放射免疫分析法测定了28例前列腺癌（Pca)及80例良性前列腺增生（BPH）患者的治疗前,后PSA含量,其中18例Pca及50例BPH患者同时测定了PSAD,结果PSA诊断Pca的灵敏度,特异性和准确度分别为85．7％,80．0％和81．4％,在鉴别Pca和BPH上PSAD优于PSA,使假阳性率由PSA的20％降到6％,但在临床应用中要注意结合其它检查进行综合分析。治疗后定期检测血清PSA对早期发现局部复发或转移,判断疗效和估测预后均有重要价值。     

Stromal Androgen Receptor Roles in the Development of Normal Prostate,Benign Prostate Hyperplasia,and Prostate Cancer

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa.The prostate contains mainly the stromal cells and epithelial cells that are separated by base members and merged in extracellular matrix. Stromal cells include fibroblasts, smooth muscle cells (SMCs), and other minor inflammatory cells, nerve cells, and endothelial cells.The prostate is developed from the endodermal urogenital sinus¹ that contains an outer layer of embryonic connective tissue urogenital sinus mesenchyme (UGM) and an inner layer of urogenital sinus epithelium (UGE).¹ The initial step of prostate development in UGM involves the differentiation of fibroblasts and SMCs,¹ and in response to the UGM androgen/androgen receptor (AR) signals, UGE can grow into the surrounding stromal cells and develop into the prostate epithelial cells as part of the normal prostate development.The ability of the UGM to induce epithelial development and the developed epithelial cells, in return, to direct UGM to undergo differentiation, suggesting that the reciprocal developmental interactions between UGM and UGE might be governed by androgen/AR signals, which are essential for the development of normal prostate, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Prostate development factors, including its proliferation, differentiation, morphogenesis, and functional maintenance, are all influenced by androgen/AR signals.² Androgen/AR signals also play vital roles in the initiation and progression of BPH and PCa,^3,4 which may require the proper interaction with various AR coregulators.²AR is a member of the nuclear receptor superfamily that can be activated and translocated from cytoplasm to nucleus after binding the testosterone or dihydrotestosterone.^5–7 In prostate, AR is expressed in both epithelial and stromal tissues. The transactivated AR in nucleus may then function through modulation of various downstream target genes to influence the development and maintenance of the prostate. In addition to influencing cell growth directly, epithelial AR and stromal AR can also function through epithelial-mesenchymal transition (EMT) to influence prostate development. EMT is a process by which epithelial cells lose their cell-cell adhesion and gain migratory properties to become mesenchymal-like and/or mesenchymal stem cells. These potent mesenchymal cells may then differentiate into different cell types to influence the progression of BHP⁸ and PCa.⁹This review will focus on the discussion of the roles of stromal AR in the development of normal prostate and prostate diseases.     

Searching for Prostate Cancer Stem Cells: Markers and Methods

The cancer stem cell hypothesis postulates that a single stem-like cancer cell is able to produce all cancer cell types found in a tumor. These cells are also thought to be the causative agents of relapse following therapy. In order to confirm the importance of cancer stem cells in tumor formation and patient prognosis, their role in prostate cancer must be comprehensively studied. This review describes current methods and markers for isolating and characterizing prostate cancer stem cells, including assays for self-renewal, multipotency and resistance to therapy. In particular the advantages and limitations of these approaches are analyzed. The review will also examine novel methods for studying the lineage of cancer stem cells in vivo using transgenic mouse models. These lineage tracing approaches have significant advantages and, if a number of challenges can be addressed, offer great potential for understanding the significance of cancer stem cells in human prostate cancer.     

Establishment of Short-Term Primary Human Prostate Xenografts for the Study of Prostate Biology and Cancer

Human tissue xenograft models are currently the only tool for conducting in vivo analyses of intact human tissue. The goal of the present study was to develop reliable methods for successful generation of short-term primary tissue xenografts from benign and tumor-derived human prostate tissue. Primary human prostate xenografts were established in athymic nu/nu mice from eight of eight benign and five of five prostate cancer tissues, collected from a total of 10 patients who underwent radical prostatectomy for the treatment of prostate cancer. An average of 13 xenografts was established per specimen. Two tissue specimens were cryopreserved for >1 month before successful generation of prostate xenografts. After 1 month in vivo, xenograft tissues were harvested and examined regarding: gross evidence of vascularization; tissue morphology; proliferation; apoptosis; and expression of androgen receptor, prostate-specific antigen, and high molecular weight cytokeratins specific for basal cells in the prostate. Direct comparison of the original tissue specimen and the 1-month xenografts revealed similar histology; similar apoptotic and proliferative fractions in most cases; and comparable expression levels and expression patterns of androgen receptor, prostate-specific antigen, and high molecular weight cytokeratins. These data demonstrate that primary human prostate xenografts, benign and malignant, can be established routinely from human prostate tissue surgical specimens, and that the xenografts maintain tissue architecture and expression of key prostatic markers. The development of this methodology, including the technique for cryopreservation of human tissue, will allow multiple (successive) analyses of human prostate tissue to be conducted throughout time using a tissue sample derived from a single patient; and simultaneous analysis of human prostate tissues derived from a cohort of patients.