The effect of heparin on the initial phase of metastasis formation

Hilgard, P.; Beyerle, L.; Hohage, Roderich; Hiemeyer, V.; Kubler, Marie Dominique

doi:10.1016/0014-2964(72)90031-x

Cited by 33 publications

(12 citation statements)

References 9 publications

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“…A possible explanation is that the EEC formation is a result of only haematogenous spread whereas EIC spread could follow lymphatic pathways. The intra-aortic injection of 51Cr-labelled Walker tumour cells into SIV-S0 rats resulted in the appearance of labelled tumour cells in the thoracic duct (Hilgard et al, 1972). Since heparin is not effective in lymphatics, the spread of tumour cells in lymphatic vessels may similarly remain unaffected, thus explaining the absence of any increase in extrapulmonary intrathoracic growth.…”

Section: )1dscu Ssionmentioning

confidence: 99%

Extrapulmonary colony formation after intravenous injection of tumour cells into heparin-treated animals

Maat¹

1978

Br J Cancer

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Summary.-Recent data on extrapulmonary colony formation after heparin administration are inconclusive. A systematic study of this topic was undertaken with 4 experimental tumour systems and 2 distinct periods of reduced clotting capacity in rats and mice. I.v. injection of various numbers of tumour cells into i.p. heparinized animals leads to:(1) Significant reduction in the number of lung colonies. The effect after 9 h anticoagulation is equal to or probably greater than after 2 h.(2) The reduction in the number of lung colonies caused by heparin is independent of the number of cells injected.(3) The number of extrapulmonary extrathoracic colonies is significantly increased by heparin in 3 of the 4 tumour systems.(4) The number of extrapulmonary intrathoracic colonies is probably unaffected.(5) The increase in extrapulmonary extrathoracic colony formation is not related to the degree of reduction in lung colonies.These data lead to the conclusion that the capacity of the lung capillaries to trap tumour cells can be decreased by heparin-induced alterations in fibrin formation. This results in a lodgement of tumour cells throughout the body which is far more pronounced than in animals with normal clotting capacity. (Hilgard and Thornes, 1976;Hilgard et al., 1977). It seems logical to explain these findings by postulating reduced lodgement of circulating tumour cells in the lung. This raises the question whether cells which do not lodge in the lungs are distributed through the rest of the body and cause tumour growth elsewhere. A limited number of reports in the literature claim an increase in secondary tumours outside the lungs as a result of anticoagulation (Lawrence, Moore and Bernstein, 1953;Boeryd, 1965; Hagmar and Boeryd, 1969). Many others, however, could not find such an increase. Reviewing them (in Table V) a number of differences appear to exist between the tumours used, making comparison difficult. The present study was therefore undertaken as a systematic investigation of the effect of heparin on the distribution of i.v. introduced cells of 4 known metastasizing tumour systems in rats and mice. MATERIALS AND METHODSTumour systems.-Four syngeneic transplantable tumour systems were employed, which metastasize in a reproducible way following s.c. or i.m. injection:

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Section: )1dscu Ssionmentioning

confidence: 99%

Extrapulmonary colony formation after intravenous injection of tumour cells into heparin-treated animals

Maat¹

1978

Br J Cancer

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“…However, Hilgard et al (59) noted a decreased initial extravascular migration of intra-arterially injected tumor cells in the heparin-treated animals. These results indicate that heparin has various effects on metastasis formation, depending on the strain of tumor, and that there is a correlation between the number of tumor cells and the dose or timing of heparin administration.…”

Section: Heparin and Heparinoidsmentioning

confidence: 99%

Inhibition of the arrest of hematogenously disseminated tumor cells

1983

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Most metastases in patients occur as a result of hematogenous dissemination of tumor cells. This process of metastasis is complex and consists of several steps, foremost of which is the arrest of circulating emboli in capillary beds and the formation of a thrombus at that site. Thrombus formation in the metastasis of human cancer was described first by Billroth in 1878. It was reported that the organization of tumor cell emboli, and the subsequent penetration of tumor cells into the capillary wall, was the first stage of metastasis. Since then, many investigations and observations have been made clinically as well as experimentally to clarify the process (or mechanisms) of tumor cell arrest and how to inhibit it. Coagulative and fibrinolytic pathways were believed to have a main role in thrombus formation. However, other factors responsible for the relationship between tumor cells and the host must be also considered. Elegant and extensive studies by Fidler and Kripke demonstrated that development of metastasis is not a random process, but a selection process of specialized subpopulations of highly metastatic cells within the primary tumors. Biochemical constituents and ionic properties on cell surfaces, deformability or locomotive activities of tumor cells, as well as thrombo-plastic-fibrinolytic activities, are also important factors determining the arrest patterns of circulating tumor cells. On the other hand, host defense factors against tumor cells in the bloodstream have been attracting much attention recently in tumor immunology. Host defense factors relating the arrest of tumor cells to the establishment of metastatic foci seemed difficult to define, since many studies showed contradictory data concerning the influence of immune response on tumor cell arrest. Hemodynamic abnormality may also influence the arrest of tumor cells in the circulation. Hypercoagulability induced from host tissues is greatly associated with the arrest patterns. Platelet activities might affect thrombus formation. Nevertheless, exact explanations of the process or mechanisms inhibiting or enhancing the arrest of tumor cells after hematogenous dissemination have not been obtained. In any event, for cancer treatment, it is important to determine which substances inhibit the arrest of circulating tumor cells and how to prevent hematogenous metastasis. In this review, we will focus upon coagulative and fibrinolytic processes and then upon substances that inhibit the arrest of circulating tumor cells. Furthermore, some comments on the possible clinical applications of inhibitory substances for prevention of cancer metastasis are added.

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“…Others found that heparin inhibited uptake of radiolabelled fibrinogen into primary tumours [14] and blocked tumourinduced disseminated intravascular coagulation (DIC) in rats [15]. Heparin also prolonged the circulation time of injected tumour cells [16], blocked migration of injected tumour cells from blood vessels to lymphatic channels [17], and inhibited entrapment of tumour cells in pelvic venous plexes following tail injection in rats [18].…”

Section: Investigations In Animalsmentioning

confidence: 99%

The Use of Heparin for Treating Human Malignancies

Ornstein

Zacharski

1999

Pathophysiol Haemos Thromb

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There is a substantial amount of data implicating coagulation mechanisms in the pathogenesis of malignancy. Studies in some experimental animal models have shown that the anticoagulant heparin limits tumour growth and metastasis and prolongs survival. Experience with the effects of heparin on human malignancy is limited primarily to settings in which it was given either to prevent or to treat thrombosis in patients who also had cancer. However, these studies have shown noteworthy apparent improvement in cancer outcome with heparin, especially with low-molecular-weight heparin. There are several possible mechanisms by which heparin could potentially alter the natural history of cancer progression because of its ability to modify the cellular and molecular environment of tumour cells. This experience provides the rationale for definitive clinical trials of heparin in patients with cancer and also for further experimentation to define the mechanisms of antineoplastic activity by this familiar class of drugs.

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The effect of heparin on the initial phase of metastasis formation

Cited by 33 publications

References 9 publications

Extrapulmonary colony formation after intravenous injection of tumour cells into heparin-treated animals

Extrapulmonary colony formation after intravenous injection of tumour cells into heparin-treated animals

Inhibition of the arrest of hematogenously disseminated tumor cells

The Use of Heparin for Treating Human Malignancies

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