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The metastasis associated protein S100A4 is a small calcium binding protein that is associated with metastatic tumors and appears to be a molecular marker for clinical prognosis. Below we discuss its biochemical properties and possible cellular functions in metastasis including cell motility, invasion, apoptosis, angiogenesis and differentiation.
Peripheral bronchial carcinoma with infiltration of the right lateral thoracic wall (Pancoast tumour) was demonstrated in a 60-year-old man with breathing-related pain in the right thoracic wall of two months' duration. As part of tumour staging needle puncture of an intra-abdominal space-occupying lesion was performed, guided by ultrasonography. Histological examination confirmed it as a bronchial carcinoma metastasis. Combined radio- and chemotherapy hardly influenced tumour growth. Three months later a subcutaneous lesion became palpable in the area of the previous needle puncture which on excision proved to be a metastasis. The patient died 10 months later from the bronchial carcinoma. Percutaneous puncture of potentially malignant space-occupying lesions must be strictly indicated. The frequency of needle tract seeding is not exactly known.
We describe 2 cases of prostatic carcinoma with pulmonary metastasis. In the first case there was no lymph node or bone metastasis, and in the second case there was only one bony metastatic lesion. Presentation, etiology and management are discussed.
A woman 35 years of age suffering from cutaneous and visceral metastatic melanoma was treated with recombinant Interferon alpha 2b (rIFN alpha 2b) subcutaneously 3 X 10(6) U/m2 3 times a week for 3 months with no apparent effect on the course of the illness. Two months after IFN therapy the patient developed cerebral metastasis. A cycle of carmustine, 100 mg/day for 3 days, was given, and complete disappearance of the cutaneous and visceral, but not of the cerebral manifestations was observed. Two consolidation cycles based on vincristine, dacarbazine and lomustine were then administered. The patient died 26 months after beginning treatment with IFN and 18 months after chemotherapy for the cerebral metastasis. No trace of tumor at the cutaneous or visceral level was found at autopsy.
The mechanism of the early stage of metastasis formation by sticky blood-born cancer cells is discussed. Abnormal platelet aggregation to circulating and lodged cancer cells, as well as alterations of blood coagulation and fibrinolysis play an important role. The reducing effect of several platelet aggregation inhibitors on cancer cell stickiness and tumor embolism mortality has been investigated in rats after intravenous transplantation of 1 X 10(6) Walker-256 carcinosarcoma cells. The tested substances diminished platelet aggregation to circulating cancer cells, leading to a dose-dependent inhibition of cancer cell lodgment to the endothelium. Furthermore, some of the substances prevented lethal pulmonary tumor cell embolism which was observed in 60% of the controls. These results are interpreted by assuming an inhibition of disseminated intravascular coagulation which occured after intravenous transplantation of Walker-256 carcinosarcoma. On this basis a clinical long-term study for metastasis prophylaxis was started more than 4 years ago with one of the tested substances, the dipyridamole derivative RA 233, in 40 patients with sarcoma or malignant lymphoma of the head and neck region. The provisional results obtained in matched pairs are discussed.
1,5-Dihydro-7-(1-piperidinyl)-imidazo[2,1-b]quinazolin-2(3H)-one dihydrochloride hydrate (DN-9693), a new c-AMP: phosphodiesterase inhibitor was examined for its inhibitory effects on platelet aggregation induced by metastasizing tumor cells and on blood-borne metastases of these tumors. 1-3 microM of DN-9693 completely inhibited platelet aggregation induced by B16 melanoma subline BL6 and Lewis lung carcinoma (3LL) cells. Platelets prepared from mice intravenously or orally administered with DN-9693 failed to aggregate after the addition of BL6 cells. Intravenous injection of DN-9693 was effective in protecting the mice inoculated with 1 X 10(6) BL6 cells against acute pulmonary embolic death. Either intravenous or oral administration of DN-9693 (1-10 mg/kg) sufficiently suppressed thrombus formation and subsequent pulmonary metastasis caused by intravenously inoculated BL6 or 3LL cells. Spontaneous pulmonary metastasis of 3LL was also inhibited by DN-9693. Continuous administration of DN-9693 during and after surgical excision of the primary tumors was the most effective treatment against the development of pulmonary metastases of 3LL.
To clarify the mechanism of cancer metastasis, new animal model of the spontaneous metastasis was established. A spontaneously metastasized lung tumor from an intraperitoneally inoculated rat stomach cancer, which was induced from a single clone, was inoculated subcutaneously in the syngeneic rats. Tumors produced again in the lung were passed subcutaneously to produce a variant with high metastatic potential. The number of the spontaneously metastasized foci of the lung from subcutaneously inoculated tumor line with high metastatic potential was 20 times more than that of a control line. This difference of metastatic potential is independent of the tumor volume at a primary site, and can not be ascribed to the process after the arrest of tumor cells in the pulmonary capillary bed, but to that of the invasion into the vessel at the primary site. Considering that the parent cell line used in this experiment had already been cloned, our result seemed to indicate that the adaptation of tumor cells to the biological environment enhanced the metastatic potential, i.e., the metastatic potential is modulated by an epigenetic change.
The detectability and signal intensity on MR imaging of mediastinal and hilar lymph nodes were studied in cases of lung cancer. Additionally, short inversion time inversion recovery (STIR) images and pathologic findings were compared. In the detection of resected metastatic mediastinal and hilar lymph nodes (n = 146), the STIR image (82%) was superior to the T1-weighted image (71%) and the T2-weighted image (60%). On STIR imaging, 212 (60%) of 412 resected non-metastatic mediastinal nodes and 38 (33%) of 116 resected non-metastatic hilar lymph nodes were detected. Characteristics of signal intensities of metastatic nodes were mainly low on T1-weighted images, high on T2-weighted images, and very high on STIR images. The rate of these characteristics of signal intensity of metastatic nodes was 59%. However, the rate of very high signal intensity of metastatic nodes on STIR imaging was 81%. Pathologically, lymph nodes with high or very high signal intensities on STIR images were metastatic, reactive and hyperplastic, or non-metastatic. Lymph nodes with slightly high signal intensity or high intensity with a low focus on STIR images were anthracotic, anthrasilicotic, caseous necrotic, calcified, or fibrotic. Thus, when the signal intensity of a lymph node was decreased on the STIR image, there was no definite evidence of metastasis excluding micro-metastasis or coagulation necrosis of a metastatic tumor. We conclude that the signal characteristics on STIR imaging are useful for distinguishing between macro-metastatic and non-metastatic lymph nodes when enlarged nodes are detected by various other types of medical imaging.
Occult prostatic carcinoma (carcinoma diagnosed because of the presence of metastasis) is commoner and commoner; the sites for metastatic disease are progressively more diverse. This is partially due to the longer life of the general population and to the better expectative of life for oncologic patients with modern treatments. We report the first case to our knowledge, of occult prostatic carcinoma diagnosed in a patient with a parenchymatous acute renal failure secondary to diffuse metastatic infiltration. We also review other atypical locations of metastasis from prostatic carcinoma reported in the literature and discuss the ways of spread in these cases.
Natural antioxidants have been shown to be rich sources of microchemicals with the potential to prevent human cancers. We examined whether dietary supplement of a fermented grain food mixture (AOB), which has been shown to have a strong antioxidative effect, may protect against colon cancer metastasis. At day 5 of AOB (6.5%) supplementation in a basal diet, the rat colon cancer cells (RCN-H4) were injected beneath the capsule of the spleen and one min later rats were splenectomized. All rats without AOB supplementation had multiple liver metastases. However, the number and the size of liver tumors were reduced by about 80% in AOB group. Combined use of cisplatin and AOB enhanced an anti-metastatic effect. The inhibition of liver metastasis by AOB was caused by the regulation of cell cycle. This product may be used as an adjuvant in the therapy of malignant neoplasia.
It has been proposed that a 356 amino acid protein encoded by the MIM (Missing In Metastasis) gene on Chromosome 8q24.1, is a bladder cancer metastasis suppressor. Recently, Machesky and colleagues [Biochem. J. 371 (2003) 463] identified MIM-B, a 759 amino acid protein, of which the C-terminal 356 amino acids are almost identical to MIM. Importantly, PCR primers and Northern Blotting probes used in the studies of MIM in bladder cancer did not distinguish between sequences specific for MIM or MIM-B, thus the importance of either protein to bladder cancer remains unclear. We have used primer sequences specific for either MIM or MIM-B to explore the possible functional significance of MIM and MIM-B to bladder cancer cell behaviour. We have compared MIM and MIM-B mRNA levels in a non-tumourigenic, non-invasive, transformed uro-epithelial cell line versus 15 bladder cancer cell lines of differing in vitro invasive abilities, as well as in five cell lines clonally isolated from the BL17/2 bladder tumour cell line, whose in vitro and in vivo invasive abilities have been determined. MIM and MIM-B mRNA levels varied widely between cell lines. Down-regulation of MIM and MIM-B occurred in 6/15 (40%) lines but lines showing down-regulation differed between MIM and MIM-B. Reduced levels of MIM and MIM-B in BL17/2 were further reduced in 2/5 (40%) sublines (MIM and MIM-B). Importantly, there was no association between MIM or MIM-B expression and invasive behaviour in vivo or in vitro. Treatment of representative cell lines with 5-aza-2-deoxycytidine failed to induce MIM or MIM-B expression. Furthermore, there was no association between MIM or MIM-B mRNA levels and p53 functional status. Our data indicate that down-regulation of MIM and/or MIM-B expression can occur in bladder cancer cell lines but is not associated with increased invasive behaviour. Our data also suggest that in those cell lines with reduced levels of MIM and MIM-B mRNA, down-regulation is unlikely to be due to promoter hypermethylation or loss of p53 function.
OBJECTIVE: The aim of this study was to estimate the time when pulmonary metastases began to grow in colorectal cancer (CRC) patients with isolated synchronous liver metastasis based on the tumor doubling time (DT). METHODS: We examined 23 pulmonary metastases in 14 patients detected after resection of liver metastases from CRC (group 1) and 19 pulmonary metastases in eight patients detected after initiation of hepatic arterial infusion chemotherapy for synchronous unresectable liver metastases (group 2). The regression line was determined from the chest X-ray films, and the DT was calculated. RESULTS: We estimated the DTs of pulmonary metastases as 65.0 +/- 28.9 and 76.2 +/- 23.0 days in groups 1 and 2, respectively, and the time when pulmonary metastases began to grow as 16-1418 and 112-1464 days before the resection of liver metastases for 19 lesions in 12 out of 14 patients of group 1 and before resection of primary CRC in group 2, respectively. CONCLUSION: It appears that in some CRC patients in whom the metastatic site is considered to be limited to the liver at diagnosis, occult pulmonary metastasis has already taken place.
A reproducible tumor model for liver metastasis has been developed from murine L5178Y lymphoma line by sequential cycles of subcutaneous inoculation of liver tumor cells, that were originally generated in livers of female (BALB/c x DBA/2)F1 mice by injecting the parental cells into the tail vein. This variant (L5178Y-ML) metastasized predominantly to the liver after intravenous or subcutaneous injection. The livers of the animals killed 9 days after intravenous implantation of 5 x 10(5) tumor cells were about 3 times the weight of control livers. All tumor-bearing mice died 10 to 12 days after inoculation. Subcutaneous implantation of L5178Y-ML in the side flank of mice induced metastatic nodules spontaneously in the livers. The tumor cells proliferated more in livers than in the implanted sites, compared with the parental L5178Y cells. The effects of 5-fluorouracil, mitomycin C, cis-platinum and doxorubicin on the liver metastasis of L5178Y-ML were examined at subtoxic doses; 5-fluorouracil was the most effective in both inhibiting the tumor growth in livers and prolonging the survival period of mice. This model provides a useful tool for the experimental therapy of hepatic tumors in mice.
Brain metastasis is an uncommon complication of differentiated thyroid carcinoma. Even more, cerebellar metastases from papillary thyroid carcinoma (PTC) are exceptional. We report a 69-year-old male patient with infiltrative PTC who developed high levels of thyroglobulin (Tg) and deteriorated neurological symptoms four years after the initial diagnosis. Computerized tomography (CT) of the brain demonstrated a cerebellar mass and the patient underwent surgery. Pathology revealed metastasis from PTC. Immunochemistry was positive for Tg. The patient had no other sites of distant metastases. Although PTC has generally a good prognosis, metastases to the cerebellum can occur, even as the first metastatic site, despite the fact that appropriate therapy (surgery, radioactive iodine therapy, TSH suppression therapy, chemotherapy and external radiotherapy) had been given for the primary tumour.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that frequently metastasizes and that overexpresses transforming growth factor-beta s (TGF-beta s). To determine whether TGF-beta s can act to enhance the metastatic potential of PDAC, PANC-1 human pancreatic cancer cells were transfected with an expression construct encoding a soluble type II TGF-beta receptor (sT beta RII) that blocks cellular responsiveness to TGF-beta 1. When injected s.c. in athymic mice, PANC-1 clones expressing sT beta RII exhibited decreased tumor growth in comparison with sham-transfected cells and attenuated expression of plasminogen activator inhibitor 1 (PAI-1), a gene associated with tumor growth. When tested in an orthotopic mouse model, these clones formed small intrapancreatic tumors that exhibited a suppressed metastatic capacity and decreased expression of plasminogen activator inhibitor 1 and the metastasis-associated urokinase plasminogen activator. These results indicate that TGF-beta s act in vivo to enhance the expression of genes that promote the growth and metastasis of pancreatic cancer cells and suggest that sT beta RII may ultimately have a therapeutic benefit in PDAC.
Percutaneous radio-frequency ablation (RFA) of liver tumors has been reported to be an effective approach. Skin implant metastases have been described after RFA of hepatocellular carcinoma. A 56-year-old man underwent resection of the transverse colon for an adenocarcinoma (pT3N2M0) following by adjuvant chemotherapy. He developed multiple liver metastases and underwent RFA. Six weeks after RFA, the patient noticed a painful skin lesion at the entrance side of the probe in the right upper abdominal quadrant. Ultrasound examination and computed tomography scan revealed an intracutaneous tumor of 2-cm diameter. The tumor was excised and revealed a metastasis of the previously described adenocarcinoma. CPT-11 monotherapy was started; however, due to tumor progression, the patient died 35 months after colonic resection and 10 months after RFA. This is the first case of an implant skin metastasis after RFA of secondary liver tumors. Although RFA is a promising option in the palliation of such tumors, such rare complications have to be considered.
For prophylactic therapy to inhibit hepatic metastatic recurrence after surgical treatment of gastro-intestinal carcinomas, the effects of OK-432, a biological response modifier (BRM), were examined with inoculation of tumor cells and administration of OK-432 via portal vein. Experiments with the inhibition of liver metastasis were performed as follows. The animals were divided into five groups. Group 1: 1.0 KE of OK-432 was given intraportally 5 minutes after injection of 5.0 X 10(6) tumor cells per rat via the portal vein. Group 2: Non-medicated group, only 5.0 X 10(6) tumor cells per rat were injected into portal vein, as the control for group 1. Group 3: 0.5 KE of OK-432 and 2.5 X 10(6) tumor cells per rat were used. Group 4: 1.0 KE of OK-432 and 2.5 X 10(6) tumor cells were used. Group 5: Non-medicated group, injected with 2.5 X 10(6) tumor cells as the control group for groups 3 and 4. Colonies of metastases in the liver of each group were examined by autopsy on the 30th day after treatment. Metastases were observed in 75% of group 1, 100% of group 2, 58.8% of group 3, 64.3% of group 4 and in 90% of group 5. For the investigation of the mechanisms to inhibit these liver metastases, 51Cr labeled AH60C tumor cells were injected into the portal vein, and the remained of radioactivity in rat liver was examined. The result showed that OK-432 injected into the portal vein did not directly kill the lodging tumor cells. To prove the morphological evidence of inhibition of hepatic metastasis, the changes of tumor cells were microscopically observed.(ABSTRACT TRUNCATED AT 250 WORDS)
In a 52 years old man a backward epilepsy revealed a left fronto parietal tumor. The histopathological study shows that it is a meningial tumor composed around by meningocytic proliferation with a metastasis of lung cancer in the middle. This fact was proved only two months after neurosurgical intervention. Thirty three cases of cancer with metastasis in an intracranial primitive tumor have been collected in the literature. The authors study the clinical aspects and etiopathogenic hypothesis of this surprising anatomopathological fact.