Bone metastasis as a non-stochastic process

Bone metastasis as a non-stochastic process

Mew frypow (1989)29.279281 @ LtqrmmGroupUK Ltd1989 Bone Metastasis M. CHIGIRA, as a Non-Stochastic Process K. NODA and H. WATANABE Department of ...

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Mew frypow (1989)29.279281 @ LtqrmmGroupUK Ltd1989

Bone Metastasis M. CHIGIRA,

as a Non-Stochastic



Department of Orthopedic Surgery, Maebashi, Gunma, 371 Japan

Gunma University

School of Medicine,

3- 39-22 Showa,

Abstract - Bone metastasis may be considered a non-stochastic process, since the blood flow in bone is lower than that in other organs and most cancers do not have a tendency to metastasize to bone in in vivo experiments. Furthermore, the experimental model of bone metastasis, based on the ligation of major venous flow, can not explain the widespread bone metastasis which is commonly observed in clinical cases. These observations may be explained by the hypothesis that tumor cells have a phenotype for translocating to specific tissues and that tumor cell growth is controlled by the microenvironmental factors in situ.

Introduction The biology of bone metastasis is poorly understood. This is, in part, due to the lack of good animal models (l), although the skeleton is the most common site of metastasis of prostate and breast cancer (2, 3). Many animal models of cancer have been developed. However, only in a small number of these has the tumor been reported to metastasize to bone (4-6). Batson and Shevrin proposed that prostate tumor cells only spread to the skeleton via the vertebral venous plexus under conditions of increased intra-abdominal pressure or of ligation of the inferior vena cava (1, 4). These data suggest that bone metastasis is not a stochastic process in nature. Discussion Lymphatic





vascular plexuses but their presence within the bone substances has never been convincingly demonstrated (7, 8), although lymphangioma of the bone has rarely been reported (9). Lymphatic flow is a centrifugal process, if it is present, since venous blood flow is similar (10). Retrograde metastasis in lymphatic channels is rare, and most cancers arise in the abdomen and thorax. Under these conditions, it is considered that metastasis via lymphatic channels is negligible in bone metastasis and that the vascular channel is the major root of “blood-borne” metastasis to bone. The average value for bone blood flow which has been proposed by Shim and Gross as about 10 ml/min/lOO mg appears reasonable (11-16). Total skeletal blood flow is under 10 per cent of the cardiac output, although the skeletal weight represents approximately 10% of the body weight in adults (14, 15). These values are much lower than those for the lung,


280 liver, kidney, and brain. It is suggested that blood flow may not be a major factor in bloodborne metastasis. A unique vascular system called the Haversian capillary has been reported (10). However, this transcortical system can not play an important role in bone metastasis, since cortical bone is not a primary area in bone metastasis, although the central medullary sinus is one of the sinusoids reported elsewhere (10). Bone is not the first capillary bed encountered after the extravasation of cancer cells, because of their anatomical location. It is difficult for us to explain the high incidence of cancer me.tastasis with the anatomical uniqueness of bone. Coffey and Isaacs demonstrated that highly metastatic carcinoma lines do not have a tendency to metastasize to bone (5, 6). Several authors showed that the increaied intra-abdominal pressure and the ligation of the vena cava inferior after intravenous inoculation of tumor cells induced vertebral metastasis (1, 4, 17, 18), although injection of the cells from the parent line subcutaneously or via the tail vein without caval occlusion did not result in bone lesions these experiments can be (19). However, considered as a model of metastasis to the lumbar spine, and can not explain the widespread bone metastasis which is more common in clinical experience (3). Metastasis to the skull, cervical spine, and long bones will not be simulated by this method, furthermore, venous obstruction can rarely be shown in the patients with cancer. These animal models are not acceptable for natural metastasis. In animal experiments, the preference of organ and tissue can not be explained by a sequential, selective and stochastic process (20-25), although these processes have been fully discussed (26-29). The initial distribution of tumor cells in an organ capillary can not explain the outcome of metastasis, and vascular anatomy is not sufficient to explain all aspects of tumor dissemination (30-32). Circulating tumor cells may show a preference for certain ectopitally transplanted organs (33-35). Furthermore, after intra-arterial injection, each tumor appears to establish its own metastatic pattern (36). Actually, Fidler established several melanoma cell lines that metastasize predominantly to the brain, although these lines did not produce a mass in the lung after inoculation via the tail vein (37). The authors also demonstrated that highly metastatic clones lost their tumorigenicity at the subcutaneous inoculation site (38). In 1889,


Paget proposed the ‘seed and soil’ hypothesis (23). The exact mechanisms by which the organ environment is able to modulate the proliferation of tumor cells is unclear (39), although this hypothesis has received considerable support from experimental systems (33, 34, 39, 40) and human studies (41, 42). These observations can be explained by the character of the tumor cell (38) and by the growth control in situ (30, 38). For example, some tumor cells most often of lymphoid or macrophage origin, do not grow in the first capillary bed encountered after intravenous injection (33-35). These data suggest that the growth of metastatic cells is inhibited in the first capillary bed such as the lung and liver. The microenvironmental cell-to-cell interaction which controls the tumor growth in situ, should be studied further. Acknowledgements We are very grateful to Drs Toru Shimizu and Satoru Arita, and Prof. Eiichi Udagawa, Department of Orthopedic Surgery, Gunma University, for their valuable discussion. ThiH work was financially supported by the Scientific Research Grant C-62570675 from the Japanese Ministry of Education.

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