Gary D. Grossfeld

Bio: Gary D. Grossfeld is an academic researcher from Bristol-Myers Squibb. The author has contributed to research in topics: Prostate cancer & Prostatectomy. The author has an hindex of 52, co-authored 109 publications receiving 8891 citations. Previous affiliations of Gary D. Grossfeld include Rancho Los Amigos National Rehabilitation Center & University of Washington.

Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.

Abstract: The present study demonstrates that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in an in vitro coculture system. Human prostatic carcinoma-associated fibroblasts grown with initiated human prostatic epithelial cells dramatically stimulated growth and altered histology of the epithelial population. This effect was not detected when normal prostatic fibroblasts were grown with the initiated epithelial cells under the same experimental conditions. In contrast, carcinoma-associated fibroblasts did not affect growth of normal human prostatic epithelial cells under identical conditions. From these data, we conclude that in this human prostate cancer model, carcinoma-associated fibroblasts stimulate progression of tumorigenesis. Thus, carcinoma-associated fibroblasts can direct tumor progression of an initiated prostate epithelial cell.

Malignant Transformation in a Nontumorigenic Human Prostatic Epithelial Cell Line

Abstract: The human prostatic epithelial cell line BPH-1 is normally nontumorigenic in nude mice. The present report demonstrates that this cell line can be permanently transformed by its microenvironment to become tumorigenic. The establishment of a series of tumorigenic sublines based on this parental cell line is described. BPH-1 cells were induced to form tumors either by recombination with human prostatic carcinoma-associated fibroblasts (CAFs) or by exposure to carcinogenic doses of testosterone and estradiol (T+E2) after recombination with rat urogenital sinus mesenchyme. Epithelial cells isolated from these tumors were established as cell strains in culture. When regrafted to nude mouse hosts epithelial cells isolated from CAF- or T+E2-induced tumors were found to be consistently tumorigenic even in the absence of CAF or T+E2. The T+E2-induced cell strains have been designated BPH1(TETD)-A and -B and the CAF-induced strains are designated BPH1(CAFTD)-01 through -08. In vitro, the cells had an epithelial morphology with a less well-defined cobblestone pattern than the parental line. They express SV40 large T antigen, confirming their derivation from the parental BPH-1 line. The BPH1(CAFTD) strains formed colonies in soft agar, whereas the parental BPH-1 cells and the BPH1(TETD) sublines did not. There was no immunocytochemically detectable expression of androgen (AR), alpha-estrogen (ERalpha), or progesterone (PR) receptors by the parental BPH-1 cell line or by any of the tumor-derived cell strains. The cells uniformly coexpressed both basal and luminal cell-type cytokeratins and the basal cell marker p63. When grafted beneath the renal capsule of athymic mouse hosts, all of the tumor-derived cell strains consistently formed tumors. These were predominantly poorly or moderately differentiated squamous or adenosquamous tumors, similar in organization to the primary tumors from which the cell strains were derived. The cell strains continued to express both basal- and luminal-type cytokeratins in vivo. Some of the cell strains also coexpressed vimentin. E-cadherin expression was absent from many of the cells, although patches of cells expressing this marker were seen. The cells continued to express SV40T antigen. These cell strains, which are all derived from a common nontumorigenic progenitor, represent a useful resource for examining genetic and phenotypic changes during carcinogenesis.

National Practice Patterns and Time Trends in Androgen Ablation for Localized Prostate Cancer

Abstract: Background Recent reports have suggested that growing numbers of patients with localized prostate cancer are receiving androgen deprivation therapy as primary or neoadjuvant treatment, yet sparse clinical evidence supports the use of such treatment in some contexts. We describe national trends in the use of androgen deprivation therapy for localized disease and identify sociodemographic variables that are associated with its use.

Thrombospondin-1 Expression in Bladder Cancer: Association With p53 Alterations, Tumor Angiogenesis, and Tumor Progression

Abstract: Background Thrombospondin-1 (TSP) is a 430-kd glycoprotein that is an important component of the extracellular matrix and is known to be a potent inhibitor of angiogenesis (ie, formation of new blood vessels) both in vitro and in vivo Several reports suggest that TSP possesses tumor suppressor function, possibly through its ability to inhibit tumor neovascularization It has recently been shown that TSP expression is enhanced by the product of the p53 gene (also known as TP53) Purpose We examined the role of TSP expression in tumor recurrence and overall survival in patients with invasive bladder cancer We also examined the relationship between alterations in p53 protein expression, TSP expression, and tumor angiogenesis Methods Tumors from 163 patients (with a median follow-up of 77 years) who underwent radical cystectomy for invasive transitional cell carcinoma of the bladder (63 patients with organ-confined disease and no lymph node involvement, 48 patients with extravesical extension of the disease and no lymph node involvement, and 52 patients with metastasis to regional lymph nodes) were examined for TSP expression by immunohistochemistry, utilizing monoclonal antibody MA-II, which recognizes an epitope in the amino-terminal region of TSP For each tumor, microvessel density counts and p53 protein expression status (via immunohistochemistry) were also determined TSP expression was graded as low, moderate, or high without knowledge of clinical outcome, p53 status, and microvessel density count; tumors with moderate and high TSP levels were considered as one group Groups of patients were compared by Kaplan-Meier product limit estimates of overall survival, the complement of cumulative incidence curves for recurrence-free survival, and the stratified logrank test Reported P values are two-sided Results TSP expression was significantly associated with disease recurrence (P = 009) and overall survival (P = 023) Patients with low TSP expression exhibited increased recurrence rates and decreased overall survival TSP expression was an independent predictor of disease recurrence (P = 002) and overall survival (P = 01) after stratifying for tumor stage, lymph node status, and histologic grade, but it was not independent of p53 status TSP expression was significantly associated with p53 expression status (P = 001) and microvessel density counts (P = 001) Tumors with p53 alterations were significantly more likely to demonstrate low TSP expression, and tumors with low TSP expression were significantly more likely to demonstrate high microvessel density counts Results of an analysis of variance were compatible with the hypothesis that p53 affects tumor angiogenesis by regulating the level of TSP expression Conclusions and implications These data support the concept that TSP may possess a tumor-inhibitory function TSP may act, in part, through the regulation of tumor neovascularity These results may also provide insight into one mechanism by which p53 exerts its tumor suppressor effects, ie, through the control of tumor angiogenesis

Effect of p21WAF1/CIP1 Expression on Tumor Progression in Bladder Cancer

Abstract: Background: Altered expression of p53 protein is an important predictor of progression in bladder cancer. The action of p53 on cell cycle regulation is mediated, in part, through expression of the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 (p21). Loss of p21 expression may, therefore, contribute to tumor progression. We sought to determine the relationship between p21 expression in bladder cancer and disease progression. Methods: Tumor specimens were obtained from 242 patients who underwent cystectomy for bladder cancer. Median follow-up was 8.5 years (range, 0.1‐11.8 years). Nuclear p21 status was determined by immunohistochemistry and was then analyzed in relationship to the probability of tumor recurrence, overall survival, and tumor p53 status. Reported P values are two-sided. Results: Nuclear p21 expression was detected in the tumors of 156 (64%) of the 242 patients. Patients with p21-positive tumors had a decreased probability of tumor recurrence (P<.00001) and an increased probability of overall survival (P<.00001) in comparison with patients with p21-negative tumors. In a multivariable analysis, p21 expression was an independent predictor of tumor recurrence (P = .0017) and of survival (P = .006) when assessed with tumor grade, tumor stage, lymph node status, and p53 status. p21 expression was associated with p53 status (P<.001); 56% of tumors with p53 alterations showed loss of p21 expression, whereas 79% of tumors expressing wildtype p53 were p21 positive. Patients with p53-altered/p21negative tumors demonstrated a higher rate of recurrence and worse survival compared with those with p53-altered/ p21-positive tumors (P<.0001). Patients with p53-altered/ p21-positive tumors demonstrated a similar rate of recurrence and survival as those with p53-wild type tumors. Conclusion: Loss of p21 expression is a statistically significant and independent predictor of bladder cancer progression. Maintenance of p21 expression appears to abrogate the deleterious effects of p53 alterations on bladder cancer progression. [J Natl Cancer Inst 1998;90:1072‐9]

Microenvironmental regulation of tumor progression and metastasis.

Abstract: Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

Fibroblasts in cancer

Abstract: Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

Microenvironmental regulation of metastasis

Abstract: Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.