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Athanasou, NA; Wells, CA; Quinn, J; Ferguson, DP; Heryet, A; McGee, JO'D
doi: 10.1038/bjc.1989.102pmid: 2713238
The origin and nature of osteoclast-like multinucleated giant cells (OMGCs), in extraskeletal neoplasms, is uncertain. The ultrastructure, antigenic phenotype and function of OMGCsm in a breast carcinoma were studied in order to clarify the relationship between OMGCs, osteoclasts and other cells of the mononuclear phagocyte system (MPS). OMGCs resorbed cortical bone in a manner similar to osteoclasts. However, unlike osteoclasts, OMGCs did not possess a ruffled border or clear zone, and expressed HLA-DR and Fc receptors and CD14, CD16, CD18 and CD11 (p150,95) antigens. In addition, OMGCs failed to respond morphologically to calcitonin and were directly stimulated by parathyroid hormone (PTH) to increase bone resorption. These findings suggest that OMGCs are a specific type of macrophage polykaryon distinct from both osteoclasts and other types of inflammatory polykaryon. Occasional smaller (20-25 microns) macrophage-like cells were also associated with resorption pits. Bone resorption by OMGCs isolated from the breast indicates that a cell of the MPS can be transplanted to a new tissue location and perform a highly specialised function appropriate to an MPS cell of that tissue (i.e. the osteoclast). PTH stimulation of bone resorption by OMGCs suggests that PTH or a PTH-like protein, may be involved in the bone resorption and consequent hypercalcaemia associated with metastatic breast cancer.
doi: 10.1038/bjc.1989.103pmid: 2469452
Chromosome damage in vitro after bleomycin treatment during the late S and G2 phases of the cell cycle was studied in the peripheral lymphocytes of 19 untreated patients with primary testicular tumours and 22 age-matched healthy men with no excess of cancer incidence in the families. The occurrence of spontaneous chromosome aberrations was not shown to be different in the studied groups. However, in the lymphocytes treated with bleomycin, cancer patients exhibited higher numbers of break events per cell (1.06 versus 0.67, P less than 0.01) and increased frequency of cells with aberrations (55.0 versus 43.0, P less than 0.05) than control group. Aberrant cells of cancer patients had more aberrations than cells of the control sample (1.79 versus 1.53, P less than 0.01). The frequency of chromosome 1 aberrations, often encountered in cancer cells of testicular and other solid tumours, was significantly higher in lymphocytes of patients with testicular cancer (15.0 versus 8.4%, P less than 0.0001), the long arm of this chromosome being predominantly affected (12.0 versus 6.3%, P less than 0.0001). These results support the view that a genome disposed to testicular cancer is less effective in the ability to repair non-specific DNA damage in this region, more susceptible to damage, or both.
doi: 10.1038/bjc.1989.104pmid: 2469453
Mice were treated by an intravenous injection of 2 mg of the photosensitising drug meso-tetra (sulphonatophenyl) porphine (TPPS) and 24 h later a 2.5 cm length of their tails was exposed to visible light (photodynamic therapy, PDT). Using cross-sections from the centre of the treatment field, the absolute areas occupied by epidermis, dermis, hypodermis, tendon and bone, and also the total number and area of the blood vessels in the dermis and hypodermis, were compared between control and PDT-treated animals. There was a significant increase in the mean cross-sectional area of the epidermis, dermis and hypodermis following both 90J cm-2 (a dose expected to produce a low incidence of tail necrosis) and 180J cm-2 (expected to produce a 100% tail necrosis rate), on day 1 and day 5 following light exposure. The cross-sectional area of the vascular compartment was also significantly increased by day 5 at both dose levels. Differences were observed between the two doses when the total number of blood vessels were compared. There was a significant increase in the number of blood vessels by day 5 following 90 J cm-2 in both the dermis and hypodermis, but not following 180J cm-2. This appeared to be due to a significant increase in blood vessels with a cross-sectional area of less than 100 microns2 by day 5 at the lower dose. It is concluded that angiogenesis plays an important role in vascular recovery following PDT.
doi: 10.1038/bjc.1989.105pmid: 2523722
Spheroids derived from the human colon adenocarcinoma cell line, WiDr, were exposed to 10 micrograms ml-1 Photofrin II and irradiated with light (700 nm, 50 mW cm-2). Compared with exponentially growing monolayer cultures, cells in spheroids of 100, 250 and 500 microns diameter were respectively 1.8, 2.5 and 22-fold less sensitive. The small resistance of plateau-phase cultures (1.3-fold) was insufficient to account for this marked spheroid size-dependent resistance. For monolayer cultures and for spheroids of 100 and 250 microns diameter, the results were the same whether irradiations were carried out pre- or post-trypsinisation. However, there was a difference for the largest spheroid size: when irradiations were carried out pre-trypsinisation, spheroids were more resistant than when irradiations were given post-trypsinisation. Drug extraction studies showed that there was no difference in the average drug uptake between cultures of exponentially growing or plateau-phase cells, and 100 microns diameter spheroids while 250 and 500 microns diameter spheroids took up proportionally 0.5 and 0.4 as much drug. Cell contact effects, drug heterogeneity between cells, hypoxia and problems in drug penetration are suggested as possible reasons for the resistance of large spheroids to photodynamic treatment.
Guillou, PJ; Ramsden, CW; Somers, SS; Sedman, PC
doi: 10.1038/bjc.1989.106pmid: 2785396
Serum-free supernatants from in vitro maintained gastrointestinal cancer and melanoma cell lines inhibit the generation of lymphokine (IL-2) activated killer (LAK) cells in a time and dose-related manner. Concentrations as low as 5% can inhibit the generation of LAK cytotoxicity but inhibition of proliferation is not observed until higher concentrations are included in the culture system. Inhibition is not observed with supernatants from a breast cancer cell line nor with supernatants from normal cells. There was complete concordance between the capacity of the tumour cells themselves to inhibit LAK generation and the presence of inhibitory activity in the corresponding supernatant. The inhibitory factor(s) is stable after heating to 44 and 56 degrees C. Production of the inhibitory factor(s) is sensitive to metabolic inhibitors and has a molecular weight greater than 25 kD. The inhibition of LAK cell stimulation by tumour cells may partially explain the failure of adoptively transferred LAK cells and IL-2 therapy to cause tumour regression in man.
van den Berg, HW; Lynch, M; Martin, J; Nelson, J; Dickson, GR; Crockard, AD
doi: 10.1038/bjc.1989.107pmid: 2713239
A 6-month exposure of ZR-75-1 human breast cancer cells to tamoxifen (1 microM rising to 2 microM). resulted in a fall in oestrogen receptor (ER) levels from 225 fmol mg protein-1 to 56 fmol mg protein-1 while progesterone receptor (PGR) concentration fell from 63 fmol mg protein-1 to undetectable levels. Sensitivity to the anti-proliferative effects of tamoxifen was unchanged. A further 6 months' exposure to 4 microM tamoxifen resulted in loss of detectable ER and PGR and development of resistance to tamoxifen. Resistant cells, designated ZR-75-9a1, displayed morphological changes consistent with the acquisition of a less well differentiated phenotype. Flow cytometric studies demonstrated that the cell cycle distribution pattern of the resistant variant growing in the presence of 8 microM tamoxifen was identical to that of the untreated parent line, which showed marked accumulation of cells in G0/G1 when exposed to 8 microM tamoxifen. The resistant phenotype was not stable if cells were transferred to complete drug-free medium, but remained stable for at least 3 months in the presence of medium lacking oestrogenic activity. ZR-75-9a1 cells differ from previously reported tamoxifen-resistant variants of the MCF-7 line which retain ER and may prove a valuable model for the study of the development and stability of tamoxifen resistance in human breast cancer.
Hills, CA; Kelland, LR; Abel, G; Siracky, J; Wilson, AP; Harrap, KR
doi: 10.1038/bjc.1989.108pmid: 2653399
Ten human ovarian carcinoma cell lines have been studied as a potential in vitro screen for the development of novel anticancer platinum complexes. Lines have been established and developed both from solid and ascitic tumours, from pretreated and untreated patients, and are available at a range of in vitro passage numbers. The biological properties of the lines were consistent with them being human, epithelial and of ovarian carcinoma origin. Using a tritiated thymidine or leucine uptake method, and a 96 hour continuous drug exposure, the lines have been calibrated against four platinum-containing chemotherapeutic agents: cisplatin, iproplatin, carboplatin and tetraplatin. Striking differences in cytotoxicity were observed across the lines for each agent. Some lines were consistently resistant, others generally sensitive, whereas some showed clear evidence of differential sensitivity to a particular agent. Statistical analysis (Spearman rank correlation) involving the six possible pairings of drugs showed that cisplatin, iproplatin and carboplatin elicit a very similar pattern of response in these lines whereas tetraplatin elicits a completely different response pattern. Similar cytotoxicity values were obtained using a soft agar cloning assay. Results using a tetrazolium dye reduction assay, however, gave somewhat higher and more variable values, particularly with tetraplatin. The thymidine uptake assay will be adopted in further studies on a selected panel of six lines. This panel encompasses the spectra of sensitivities identified for each of the four agents against the original ten lines and may provide a useful screening facility for the development of novel platinum drugs, in that it detects both cell line-determined and structure-determined differences in cytotoxicity.
Kimura, S; Sone, S; Takahashi, K; Uyama, T; Ogura, T; Monden, Y
doi: 10.1038/bjc.1989.109pmid: 2785397
The present study was undertaken to examine whether the presence of primary lung cancer could affect the antitumour activities of pleural cavity macrophages (PCM) and peripheral blood monocytes (PBM). PCM by pleural lavage and PBM were simultaneously obtained from 14 lung cancer patients not showing invasion of the pleural cavity. PCM and PBM were isolated by percoll gradient centrifugation and adherence. The lavage method yielded about 16.8 +/- 9.6 (s.e.) x 10(6) cells, which consisted of 80.7% PCM, 17.6% lymphocytes and 1.6% other cells. The cytotoxic activities of PCM and PBM against allogeneic melanoma (A375) cells were assessed by a 72h 125I-IUdR release assay. The lavaged PCM showed spontaneously high tumour cytotoxic activity which was dependent on the effector/target ratio. In 13 out of 14 cancer patients, PCM were significantly more cytotoxic to melanoma cells than PBM. In contrast, there were no significant differences in production of tumour necrosis factor (TNF-alpha) or interleukin 1 (IL-1) between PCM and PBM. When the abilities of PCM and PBM of the same patient to produce these monokines were compared, PCM produced much more TNF-alpha than PBM, thus indicating a correlation between the expression of spontaneous macrophage-mediated cytotoxicity and spontaneous TNF-alpha production by PCM. These results suggest that PCM may play an important role in host defence against invasion of the pleural cavity by cancer cells.
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