Cellular and molecular mechanisms of metastasis as applied to carcinomatous meningitis

Cancer cells as well as bacteria metastasize to the subarachnoidal space (SAS) causing meningitis. Primary brain tumors, although not forming distant metastases, disseminate via the cerebrospinal fluid and occupy the meninges. The multistep process of cancer or bacterial dissemination is regulated through molecular crosstalk between invaders and host cells. Such crosstalks establish invasion-promoter and invasion-suppressor complexes. In carcinomatous and bacterial meningitis, the participation of host cells is prominent since leukocytes and inflammatory cytokines are the major determinants of malignancy. We propose a model in which bacterial breakdown products activate endothelial cells, a process leading to leukocyte extravasation. This initiates a cascade of inflammatory processes opening up the blood cerebrospinal fluid barrier and producing access for new invaders.     

Relevance of hydroxyproline excretion to bone metastasis in breast cancer

In 181 consecutive patients with breast cancer, urinary hydroxyproline excretion has been critically evaluated in conjunction with clinical, biochemical, radiological and scintigraphic parameters. The urinary hydroxyproline/creatinine ratio is a sensitive index of the presence of bone metastases. Urinary hydroxyproline excretion is a reliable method of selecting those patients whose elevated serum alkaline phosphatase is secondary to bone disease rather than liver idsease. The estimation of hydroxyproline excretion furthermore gives information on the activity of bone metastasis, and its response to treatment, which cannot be given by radiological or scintigraphic methods. It is doubtful whether urinary hydroxyproline estimation will help to detect bone metastases before they are apparent on scintigrams. When the bone scan is doubtful, as often occurs in older subjects, hydroxyproline excretion has been found to be helpful in classifying the patient. When scintigraphy is not available, an elevation of hydroxyproline excretion, together with an elevation of Ca/cr ratio or alkaline phosphatase activity, may pre-date by several months the radiological demonstration of osseous metastases.     

Cellular and molecular mechanisms of tumor invasion

This review summarizes data on cellular and molecular mechanisms underlying phenotypical characteristics of tumor cells that determine their ability for invasion. These mechanisms include dysregulation of adhesive interactions of tumor cells with each other and with extracellular matrix, protease production, locomotion reactions of tumor cells, and induction of angiogenesis in tumor. Data on structure and functions of transmembrane adhesion molecules and their ligands, molecular composition of adhesion structures (intercellular and focal contacts), and role of adhesion molecules as transducers of intracellular signals are considered. Alterations of expression of adhesion molecules and cytoplasmic proteins in adhesion structures and hyperphosphorylation of these molecules by oncogene products are described as a precondition of invasion activity of tumor cells. The contact interaction between circulating tumor cells and vascular endothelium is considered as the important stage of the metastatic process. Secretion of proteases by tumor cells and regulation of their activity by specific stromal inhibitors are described. Function of motogens in the acquisition by a tumor cell of locomotor phenotype facilitating invasion and impairments of topographic reactions of cells playing an important role in the invasion are considered. Attention is given to mechanisms of neoangiogenesis in the tumor providing additional ways for dissemination of tumor cells.     

Bilateral testicular metastasis of cancer of the prostate

Testicular metastasis of prostate cancer rarely occurs. Bilateral localization is exceptional. We report a new case of prostate adenocarcinoma with bilateral testicular metastasis. The diagnosis was made on clinical and ultrasonic arguments, and confirmed on the pathological specimen. Treatment consisted in a bilateral orchidectomy, associated with nonsteroid androgens.     

Occult breast cancer causing axillary metastasis

Orthodontic bands form retention areas which create favourable conditions for growth of lactobacilli. This study deals with the numbers and specific species of lactobacilli in the oral cavity of teenage orthodontic patients. High numbers of lactobacilli were obtained (log 6.398 +/- 0.761 cfu/ml) and the buffer capacity of saliva indicated a high caries risk amongst these individuals but the actual DMFT values were relatively low. Homofermentative lactobacilli predominated in both plaque and saliva and particularly L. salivarius and L. casei. These two lactobacilli species indicated that these patients are at a high caries risk. Several other homofermentative and heterofermentative lactobacilli were isolated which indicated the complexity of the oral lactobacilli community in saliva and plaque.     

Sex steroid hormones and genetic susceptibility to breast and prostate cancer

In SPECT, both the noise affecting the data and the discretization of the inverse Radon transform are responsible for the ill-posed nature of the reconstruction. To constrain the problem, we propose a regularized backprojection method (RBP) which takes advantage of the relationships existing between the continuity properties of the projections and those of the reconstructed object. The RBP method involves two stages: first, a statistical model (the fixed-effect model) is used to estimate the noise-free part of the projections. Then, the filtered projections are reconstructed using a backprojection algorithm (spline filtered backprojection) which ensures that the reconstructed object belongs to a space consistent with that containing the projections. The method is illustrated using analytical simulations, and the RBP approach is compared to the conventional filtered backprojection. The effect on the reconstructed slices of the parameters involved in RBP is studied in terms of spatial resolution, homogeneity in uniform regions and quantification. It is shown that appropriate combinations of these parameters yield a better compromise between homogeneity and spatial resolution than conventional FBP, with similar quantification performances.     

Clinical usefulness of blood PICP, PINP and ICTP concentrations as bone metastasis markers in prostate cancer patients

PICP and PINP are considered markers of bone formation, and ICTP is considered to be a marker of bone resorption. We measured these three markers as indicators of bone metastasis of prostatic cancer, and assessed their clinical usefulness. Serum PICP, PINP and ICTP were significant higher in patients with bone metastasis than localized cancer or controlled bone metastasis. Serum PSA increased initially with the LH-RH agonist during the course of bone metastasis. All these markers were subsequently observed to increase. Change in PICP of patients with bone metastasis was slight compared to PINP during endocrine treatment. Serum PICP, PINP and ICTP reflect the extent of metastasis in bone and are useful for monitoring the response of this condition to therapy.     

Strontium-89 for palliation of pain from bone metastases in patients with prostate and breast cancer

We have used strontium-89 chloride (89Sr) for the palliative treatment of metastatic bone pain. Seventy-six patients (50 males with prostate carcinoma and 26 females with breast cancer) were treated with 148 MBq of 89Sr. Sixteen patients were retreated, receiving two or three doses; the total number of injected doses was consequently 95. The Karnofsky performance status was assessed and pain and analgesia were scored on scales of 9 and 5 points, respectively. The efficacy of 89Sr was evaluated at 3 months of treatment. Three levels of response were considered: good - when there was an increase in the Karnofsky status and a decrease in the pain score (equal to or higher than 4) or analgesic score (equal to or higher than 1); partial - when there was an increase in the Karnofsky status and a decrease in the pain score (2 or 3 points) without significant changes in the analgesic score; no response - if no variation or deterioration in these parameters was observed. In prostate cancer patients, the response was good in 64% of cases and partial in 25%, and there was no response in the remaining 11%. In breast cancer patients, the response was good in 62% of cases and partial in 31%, and there was no response in the remaining 8%. Duration of the response ranged from 3 to 12 months (mean 6 months). In the patients who were retreated the effectiveness was as good as after the first dose of 89Sr. A decrease in the initial leucocyte and platelet counts was observed after the 1st month of treatment, with a gradual partial to complete recovery within 6 months. It is concluded that 89Sr is an effective agent in palliative therapy for metastatic bone pain in patients with prostate or breast carcinoma. If required, retreatment can be administered safely and with the same efficacy as is achieved by the first dose.     

Bone metastasis with superimposed osteomyelitis in prostate cancer

The following case of a male patient with a history of prostate cancer suffering from pain and swelling in the right mandibular area illustrates the well-known diagnostic problem of a superinfected tumor. Orthopan tomography and CT showed no defects in bone structure or smooth tissue. Whole-body bone scanning showed increased tracer uptake in the mandibular bone and in several other locations in the skeletal system. Antigranulocyte immunoscintigraphy showed increased uptake over the right mandible, whereas the other metastatic sites were visualized as cold spots. A second CT scan depicted a sclerotic lesion with surrounding periostal reaction and soft-tissue swelling and was interpreted as osteomyelitis. Therefore, clinical symptoms, bone scanning, antigranulocyte immunoscintigraphy and follow-up CT resulted in a diagnosis of osteomyelitis, although open needle biopsy revealed the lesion to be prostate cancer metastasis with massive leukocytic invasion.     

Cell biology of osteoclasts and molecular mechanisms of bone resorption

The maintenance of a normal skeletal shape and bone mass closely depends on a normal osteoclastic activity, as do bone growth and repair. Thus, the improvement of our means of therapeutic intervention will depend on our better understanding of the molecular basis of bone resorption and of the cellbiology of the osteoclast. This review-article presents our current opinion of the molecular mechanisms of bone resorption by the osteoclast. After describing the morphological features of the osteoclast, aspects as cell mobility, attachment, enzymesynthesis, transmembrane transport, osteoclast differentiation and function, as well as the protooncogenes c-src and c-cbl and their role for bone resorption are presented in detail.     

Central nervous system metastasis in breast cancer

BACKGROUND AND PURPOSE: Central nervous system (CNS) metastasis occurs in at least 30% of patients with breast cancer. Standard treatment is the same as in other solid tumors, though clinical behavior, and sensitivity to radiation therapy (RT) and to chemotherapy may differ considerably. Most of these patients die within a few months, but a substantial subgroup may survive a year or more. The last decade has given rise to new diagnostic methods, new surgical and radiotherapeutic techniques, and the clinical evidence of a chemotherapy permissive blood-brain barrier in CNS metastases. The literature was reviewed to assess the clinical impact of early diagnosis, recognition of prognostic factors, and of the recently developed therapeutic approaches. MATERIAL AND METHODS: Review of the literature on CNS involvement in breast cancer focusing on clinical studies on early diagnosis, new modes of treatment, and factors influencing outcome. RESULTS: Although randomized studies are still awaited, systemic chemotherapy seems a valuable alternative for RT of brain metastases in selected cases. In meningeal carcinomatosis, long survival may be independent of intraventricular chemotherapy. Neurotoxicity of intensive intraventricular treatment is considerable. In epidural metastasis, early diagnosis with prompt start of treatment remains the crucial factor for outcome. Radiation therapy is the mainstay of treatment of epidural metastasis, but new surgical techniques and even systemic chemotherapy should be considered in selected cases. CONCLUSIONS: Recognition of prognostic factors combined with appropriate use of various recently developed therapeutic possibilities will improve the clinical outcome including better local tumor control and less treatment-induced neurotoxicity in a considerable number of patients with CNS metastasis from breast cancer.     

The clinical usefulness of urinary pyridinoline and deoxypyridinoline as potential markers of bone metastasis in patients with prostate cancer

The aims of this study were to investigate the effects of paracentesis on uterine and intraovarian haemodynamics by colour Doppler ultrasound and the influences of repeated paracentesis on pregnancy outcome in severe ovarian hyperstimulation syndrome (OHSS). Forty-one abdominal paracenteses were performed on seven pregnant women with tense ascites and eight thoracocenteses were performed on three pregnant women with pleural effusion. Pulsatility index (PI) and maximum peak systolic velocity (MPSV) of uterine and intraovarian arteries were measured before and after each intervention. The mean PI of uterine arteries was decreased significantly after paracentesis, but not after thoracocentesis. Furthermore, uterine PI was decreased in 13 out of 14 (92.9%) paracenteses with <2500 ml ascites removed, compared with eight out of 13 (61.5%) with >2500 ml ascites removed. After paracentesis, there were no significant changes in the intraovarian PI and MPSV in either group. The 24-hour urine output increased significantly in the paracentesis group, but not in the thoracocentesis group. There were no significant changes in haematocrit and electrolytes as a result of paracentesis. However, gradual falls in serum total proteins and albumin concentrations were observed in all patients after repeated paracentesis, necessitating post-paracentesis albumin infusion. There was no significant difference in miscarriage rates between the two groups. We conclude that repeated abdominal paracentesis increases uterine perfusion and has no adverse effects on pregnancy outcome in severe OHSS. Extraction of 2500 ml of ascitic fluid did not impair uterine perfusion.     

Human androgen-induced growth factor in prostate and breast cancer cells: its molecular cloning and growth properties

Androgen-induced growth factor (AIGF) has hormone-regulated properties in the mouse Shionogi carcinoma cell line. To investigate whether or not it is involved in growth of human hormone-responsive cancers, we isolated the human AIGF gene from a placental genomic library. Genomic analyses suggested that the AIGF gene was about 6.5 kilobases in length containing five exons. The deduced amino acid sequence of human AIGF was completely identical with that of the mouse. RT-PCR analyses showed that prostate and breast cancer cell lines, LNCaP, PC-3, and MCF-7, slightly expressed the AIGF gene. Recombinant AIGF enhanced the growth of the human prostate cancer LNCaP cells, and it also markedly stimulated the growth of fibroblasts. These in vitro findings suggest that AIGF might be a possible autocrine or paracrine factor in hormone-responsive cancers.     

Peripheral bone metastasis of a rare lung cancer

This article describes the case of a 54 year-old man with a rare large cell cancer of the lung who presented with a metastasis to the right hand. Radiography showed destruction of the phalanx, and histology study confirmed a metastasis of the lung cancer. Metastatic spread is discussed and compared to other metastatic diseases of the hand.     

Cell and molecular mechanisms of pathogenesis and treatment of cancer

Surgery remains the mainstay of treatment for most classes of human solid tumours, with the principal exception of lymphomas, but it is insufficient in many cases to guarantee cure. With few exceptions, recurrent and metastatic solid tumours continue to defy attempts to develop effective adjuvant therapies. Recent insights into tumour biology reveal an increasingly complex picture of cell and molecular processes which confer heterogeneity and resistance to treatment upon tumours. These insights may also yield new targets for more effective adjuvant therapies.     

Cathepsin D expression in skin metastasis of breast cancer

Cathepsin D, an aspartic proteinase, correlates with invasion and metastasis in breast cancer and with poor prognosis. In the present study, we examined the immunohistological expression of cathepsin D in both primary (5 cases) and skin-metastatic breast cancers (13 cases) and compared it to those in gastric (2 cases) and lung (4 cases), and primary eccrine cancers (3 cases). All breast and gastric cancers were adenocarcinomas. The 2 gastric cancers were poorly differentiated, while the 4 lung cancers consisted of 2 poorly differentiated adenocarcinomas, 1 poorly differentiated large cell carcinoma, and 1 moderately to poorly differentiated squamous cell carcinoma. We also surveyed the immunohistological distribution of cathepsin B, carcinoembryonic antigen, gross cystic disease fluid protein-15, c-erbB-2, and estrogen receptor. In almost all breast cancer samples, the cancer cells demonstrated strong expression of cathepsin D in the cytoplasm, but weak staining patterns with other antibodies. Gastric and lung cancer cells did not respond with cathepsin D (except one metastatic lung cancer) or the other immunohistological markers. Since cathepsin D is strongly expressed in primary and metastatic lesions of breast cancer, cathepsin D could be useful as an adjunct to a panel of immunohistochemical stains in determining the primary site of origin of metastatic cancer in the skin.     

Dietary fat and breast cancer metastasis by human tumor xenografts

Human breast cancer cell lines growing as xenografts in athymic nude mice have been used to examine the effects of dietary fat and fatty acids on tumor progression. The estrogen independent MDA-MB-435 cell line has the advantage that it metastasizes consistently to the lungs and forms quantifiable secondary nodules when injected into the mammary fat pads. With these breast cancer cells, the stimulating effects of polyunsaturated omega-6 fatty acids on both primary tumor growth and metastasis were demonstrated; in contrast, the long-chain omega-3 fatty acids were inhibitory. The model can also be adapted to examine dietary fatty acids, and inhibitors of their metabolism, as experimental adjuvant therapy after surgical excision of the primary tumors. Unfortunately, estrogen dependent human breast cancer cells do not metastasize, or do so rarely, in nude mice; in consequence, it is not possible to use the model to study estrogen-fatty acid interactions on the metastatic process. In addition to metastasis from a primary location, intravenous injection of MDA-MB-435 cells into the nude mouse host, particularly when combined with studies using Matrigel-based in vitro invasion assays, permits further dissection of the steps in the metastatic cascade which are influenced by dietary fatty acids. The results obtained by these several approaches have demonstrated distinct roles for the cyclooxygenase and lipoxygenase-mediated products of omega-6 fatty acid metabolism, and suggest new approaches to experimental breast cancer therapy.