Christopher H. Chay

Stromal factors involved in prostate carcinoma metastasis to bone

Prostate carcinoma (PC) frequently metastasizes to bone, where it causes significant morbidity and mortality. Stromal elements in the primary and metastatic target organs are important mediators of tumor cell intravasation, chemoattraction, adhesion to target organ microvascular endothelium, extravasation, and growth at the metastatic site.

A functional thrombin receptor (PAR1) is expressed on bone-derived prostate cancer cell lines

OBJECTIVES To identify genes important in prostate cancer metastatic to bone. Bone-specific metastasis is a common feature of prostate cancer and a significant cause of morbidity. METHODS To identify factors involved in organ-specific metastasis, we used cDNA microarray analysis to compare a bone-derived cell line, VCaP, with a soft tissue-derived cell line, DuCaP. Both cell lines were derived from the same patient and spontaneously passaged. RESULTS Forty-five genes were differentially expressed, and only seven of these also had increased expression in VCaP compared with normal prostatic tissue. Of these, protease-activated receptor 1 (PAR1) was verified as having increased expression by reverse transcriptase-polymerase chain reaction and Northern blot analysis, as well as by immunohistochemistry. PAR1 expression in a panel of prostate cancer cell lines demonstrated increased expression in those cell lines derived from bone metastases. Alpha-thrombin stimulation of the VCaP cells produced a dose-dependent mobilization of intracellular calcium compared with DuCaP, suggesting that PAR1 expressed on the VCaP prostate cancer cell line is functional. CONCLUSIONS These data indicate that a functional PAR1 is expressed on prostate cancer cell lines. The prostate cancer cell lines expressing PAR1 appear to have an association with increased bone metastases.

Phase II trial of paclitaxel, estramustine, etoposide, and carboplatin in the treatment of patients with hormone-refractory prostate carcinoma

Preclinical data suggest that the combination of intravenous (i.v.) paclitaxel, carboplatin, oral etoposide, and oral estramustine (TEEC) has significant activity in patients with advanced, hormone‐refractory prostate carcinoma. The authors conducted this clinical trial to evaluate the addition of carboplatin to the three‐drug combination of paclitaxel, estramustine, and etoposide (TEE).

Adjuvant and Neoadjuvant Therapy in Prostate Cancer

While surgery and radiation therapy remain the only definitive treatments for prostate cancer, single modality therapy has been associated with high failure rates in patients with aggressive disease. Although hormonal therapy has been effective in cases of metastatic disease, the timing of treatment with respect to definitive therapy remains controversial. This review will explore the efficacy of hormonal and chemotherapy in both the adjuvant and neoadjuvant settings. A MEDLINE search was performed to identify pertinent articles regarding both adjuvant and neoadjuvant therapy in prostate cancer. Articles of historical relevance in addition to those using large patient numbers with a randomized design were reviewed preferentially. Since hormonal therapy has been considered standard treatment at the time of cancer progression after definitive therapy, many of the randomized trials essentially compared adjuvant therapy to delayed therapy. Historical trials using adjuvant hormonal therapy have been limited due to difficulties in clinical staging, as well as toxicities attributed to the formulations used. More recently, hormonal therapy has been found to delay disease progression, increase disease-free survival, and decrease mortality when given immediately after prostatectomy or radiation therapy in selected patients. Neoadjuvant hormonal therapy can improve disease-free survival and local control when given before radiation therapy; it has only decreased positive surgical margins when given prior to radical prostatectomy. Although hormonal therapy given immediately after either radical prostatectomy or radiation therapy is highly effective, the side effects of persistent long-term use must be weighed for each patient. While the use of chemotherapy has been limited by the lack of active agents, newer combinations have shown effectiveness in patients with hormone refractory disease, raising the possibility of their use in the adjuvant setting.

Evidence for lectin signaling to the nuclear matrix: cellular interpretation of the glycocode.

All cells exist within a context. They are often in contact with other cells or they may be bound by the extracellular matrix (ECM). The microenvironment around a cell, including interactions with neighboring cells and the ECM, has been shown to effect morphology, DNA synthesis, and even gene expression [Gospodarowicz et al., 1978; Bissell et al., 1981]. These signals dictate how a cell responds to its surroundings. In normal tissue, cells are governed by a given set of rules such as contact inhibition and apoptosis, but transformed cells disregard these rules by forming clumps of cells, moving through complex matrices, and ignoring commands for programmed cell death. Understanding what messages cells obtain from their surroundings, how they interpret these messages, and how they respond is an important dynamic of both normal and pathologic cell biology. The tissue matrix is the physical framework connecting the components of a cell with the ECM [Isaacs et al., 1981; Fey et al., 1984; Pienta et al., 1993]. The tissue matrix is a three dimensional structure which links the chromosomes to the nuclear matrix, followed by the cytoskeleton, membrane matrix, and ECM. The nuclear matrix has several functions including determining nuclear morphology [Berezney and Coffey, 1974], providing DNA organization and scaffolding [Pienta et al., 1991], replicating DNA [Vogelstein et al., 1980], and transcribing RNA as well as directing RNA transport [Ciejek et al., 1982]. The cytoskeletal matrix is composed of intermediate ®laments (IFs), actin micro®laments, and microtubules and plays a role in cytokinesis and mitosis. IFs speci®cally have been shown to provide direct contact between the nuclear matrix and the cytoskeleton. A cell interacts with its microenvironment through the membrane matrix, proteins and glycoproteins imbedded in the plasma membrane. Protein±protein interactions have been shown to be an important component not only for cellular adhesion, but also for signal transduction. Cell surface integrins, a family of heterodimeric glycoproteins, have been well described as binding to speci®c RGD sequences found in collagen and other membrane proteins [Ruoslahti and Obrink, 1996; Gahmberg et al., 1997]. The cytoplasmic domains of integrins have been shown to bind to essential cytoskeletal proteins such as talin and a-actinin, and activate focal adhesion kinase in creating adhesion complexes. By interacting with the ECM and neighboring cells through the adhesive properties of its external domain, and the cytoskeletal framework with its cytoplasmic domain, integrins demonstrate an ability to bridge the gap between mechanical adhesion and intracellular signaling. While much focus in the ®eld of cell adhesion and ECM interactions has been placed on integrins and protein±protein interactions, we are only just beginning to understand the spectrum of protein±carbohydrate interactions. Breaking the DNA and polypeptide codes has allowed the in-depth study of the passage of genetic material, mutations of this system, and its expression into proteins. Both DNA and polypeptides represent linear codes with permutations of a limited set of units. Carbohydrates, by containing branched chains and additional sulfate, phosphate, or O-acetyl groups, have a variety of organizational

New discoveries in prostate cancer biology and treatment. 5-9 December 2001, Naples, Florida, USA.

Androgen independence and bone metastasis are lethal complications in patients with advanced prostate cancer. Presently, there is no cure for patients with androgen-independent prostate cancer. In order to develop more effective therapies for this disease, the molecular events involved in the development of androgen independence and bone metastasis must be elucidated and then targeted by therapeutic agents. Several studies presented at a recent conference on prostate cancer sponsored by the American Association for Cancer Research (AACR) provided evidence that prostate cancer metastasis to bone is mediated by the prostate cancer cell expression of molecules that allow the cells to invade, grow in and stimulate cells in the bone microenvironment resulting in an osteoblastic reaction. Androgen independence was reportedly mediated by an increased expression of survival genes following androgen ablation therapies and several molecular mechanisms involved in genetic instability. Treatment strategies are being designed to target some of the molecular events involved in androgen independence and bone metastasis. Targeting these molecular events with combinational therapies will hopefully delay the progression to androgen independence in patients with early stage disease, suppress the growth of androgen-independent cells in patients with advanced disease and enhance the chemosensitivity of androgen-independent cells.