Mechanisms of organ selective tumour growth by bloodborne cancer cells

Abstract

Summary The sites of tumour development for 6 rat tumours injected into syngeneic rats via different vascular routes was determined. Xenografts of human tumours were also injected intra-arterially (i.a.) into immunosuppressed rats.Following intravenous (i.v.) In explaining the mechanism of site selectivity by bloodborne metastasis the haemodynamic theory of Ewing (1928) stressed the importance of the mechanics of the circulation whereas the Soil/Seed hypothesis of Paget (1889) emphasized the importance of the environment in which the trapped emboli found themselves. The eventual sites of metastasis are, however, determined by both haemodynamic and soil/seed factors. Haemodynamic factors are important following the venous discharge of tumour cells since the 'organs of first encounter' are the commonest site for bloodborne metastasis -the lung after systemic venous discharge of tumour cells and the liver after portal venous discharge (Viadana et al., 1978). The present study emphasizes that the 'soil' becomes important when tumour cells have entered the systemic arterial circulation and are thereby delivered to all organs. Clinically this situation can occur when cells are released from primary or secondary lung tumours or possibly when cells released into the venous circulation manage to traverse the lung capillaries.In this paper we extend earlier data (Murphy et al., 1986) on the pattern of spread of rat syngeneic non-lymphoid and non-haemopoietic tumours following intravenous (i.v.), intraportal (i.ptl.) and intra-arterial (i.a.) injection. In our i.v. and i.ptl. studies as well as previously reported studies tumour growth is essentially limited to the 'organs of first encounter' and the study of mechanisms of site selectivity is therefore limited. In order to deliver tumour cells to all organs we have injected them intra-arterially via the intracardiac (i.c.) route. Labelled cell distribution after i.c. injection has been compared with the distribution of cardiac output (measured using the microsphere technique) in order to establish whether cells disseminate and arrest passively or whether they recirculate and localise in certain organs. The 'arterial pattern' of tumour growth after unlabelled cell injection has then been compared with the arterial distribution of labelled tumour cells to establish and quantitate the 'soil effect'.Having established a 'soil effect' after arterial injection of tumour cells we have attempted to determine the mechanisms using several approaches. Firstly a correlation of site selectivity with organ vascularity (using data obtained from the microsphere studies) was sought since there have been reports that more vascular organs might be more susceptible to metastasis (Weiss et al., 1981). Secondly the rate of autolysis of trapped labelled cells in different organs has been compared with the organs susceptibility to tumour growth. Thirdly we have intervened pharmacologically to see if site preference can be altered and finally we have rendered refractory organs susceptible to tum...

Phenotypic stability and metastatic behaviour of serially xenografted rat mesotheliomas

“…The site selectivity of metastases was thought by Ewing (1928) to be determined by haemodynamic considerations of the arterial blood supply, which could be the case in our observations, as the pleura is more invested with the bronchial arterial supply than the parenchyma (Spencer, 1985). However, the soil/seed hypothesis (Murphy et al, 1988), which emphasises the importance of the microenvironment around the metastatic cell, seems attractive since the metastatic mesothelial cells are preferentially localising at a site from which they originated, the pleura, where they ought to have the best microenvironment for continued growth. Fibrosarcoma cells with a propensity to metastasis to the lung (originally induced by methylcholanthrene) have been shown to grow preferentially on the pleura, although initially they are evenly distributed throughout the lung (Orr et al, 1988).…”

Preferential growth of bloodborne cancer cells in colonic anastomoses

“…To express a 'soil effect' numerically as a probability that a single cell will cause a deposit requires that following intracardiac injection, the cells are distributed singly within the tissues. This was shown to be the case for normal tissue by Murphy et al (1986;1988) who found that following intracardiac injection of single cell suspensions, the cells distributed in the organs singly and randomly. Individual cells were far apart and there was no possibility that the tumour formed as the concerted action of several cancer cells.…”

“…In the present study, enhancement is largely over when the trauma precedes the tumour injection by 14 days. It is noteworthy that transecting the bowel after the cells have reached the tissue does not cause detectable enhancement of tumour growth, even though tumour cells are known to remain viable for up to 24 h after trapping in tissues (Murphy et al, 1988). Enhanced tumour growth at a healing colonic anastomosis is not restricted to one tumour (MC28) as the OES5 carcinoma also grows at colonic anastomoses.…”

“…This effect is reproducible with different tumours and appears to be a feature of the behaviour of the recipient tissue rather than the tumour (Murphy et al, 1986). The resistance of the colon to growth of these experimental tumours is paralleled by the clinical observation that the large bowel is a rare site for bloodborne secondary deposits from primary malignancies elsewhere in the body.Trauma to a tissue is known to enhance the ability of that tissue to support growth of tumour either from locally implanted cells (Jones & Rous, 1914), or from cells that reached the site of injury via the circulation (Robinson & Hoppe, 1962;Alexander & Altemeier, 1964;Fisher & Fisher, 1965).Following intracardiac injection of the two tumours used in this investigation, Murphy et al (1988) found that growth occurred much more readily in healing laparotomy wounds than in the surrounding normal skeletal muscle. There have been no studies to investigate the effect of surgical trauma on the ability of the large bowel to support growth of tumour cells delivered by the circulation.…”

“…Following intracardiac injection of the two tumours used in this investigation, Murphy et al (1988) found that growth occurred much more readily in healing laparotomy wounds than in the surrounding normal skeletal muscle. There have been no studies to investigate the effect of surgical trauma on the ability of the large bowel to support growth of tumour cells delivered by the circulation.…”