The sequence of events in haematogenous metastasis from colonic carcinoma was analysed, using 1541 necropsy reports from 16 centres. The findings are consistent with the cascade hypothesis that metastases develop in discrete steps, first in the liver, next in the lungs and finally, in other sites. Deviations of necropsy findings from the cascade model are largely explained on the basis of false negative reports. In only 216 of 1194 cases was there suggestive evidence that metastatic patterns (excluding lymph nodes) were causally related to lymphatic or non-haematogenous pathways. The incidence of metastatic involvement in 'other' (quaternary) sites correlated with target organ blood-flow (ml min-) per g, only when bone marrow and thyroid were excluded. In the thyroid the incidence was lower than expected on the basis of blood flow per g tissue; this may indicate that the thyroid is an unfavourable site for metastatic growth of colonic carcinoma. In the bone marrow it is higher; the latter may be due to delivery of cancer cells via both arterial blood and the vertebral venous plexus. Recognition of this pattern of metastases in the bone marrow could be important with respect of diagnosis and therapy, in patients with colonic carcinoma.

Haematogenous metastastic patterns in colonic carcinoma: An analysis of 1541 necropsies

It has been the purpose of this article to describe recent advances in cancer metastasis research. Clinical realities and experimental approaches to the study of underlying basic mechanisms of metastasis formation were discussed. Wherever possible, results were reported which led to the development of theoretical concepts. Such results and concepts were finally evaluated in light of their possible impact for the design of new treatment strategies. Experimental findings from many diverse research fields were summarized with the help of tables, figures, and references. It was concluded that the process of metastasis is a dynamic event that can be described as a sequence of interrelated steps. Experimental results indicated that malignant cells that migrate and disseminate from the primary organ to distant sites and there eventually develop into metastases have to survive a series of potentially lethal interactions. Intimate tumor-host interactions were reported to take place all along the metastatic process. They were elucidated at the steps of angiogenesis, invasion, organ interaction, dormancy, tumor rejection, and tumor immune escape. The outcome of such tumor-host interactions seemed to depend on intrinsic properties of the tumor cells themselves as well as on the responsiveness of the host. Metastasis does not appear as a merely random process. Both clinical and experimental studies revealed that the whole process can be described more appropriately in terms of stochastic, sequential, and selective events, each of which is controlled and influenced by a number of mechanisms. With regard to therapeutic intervention, a selective event offers more possibilities than a random one because it is governed by rules that can be exploited experimentally. Various impacts from experimental studies for the design of antimetastatic cancer treatment strategies were discussed. Sequential steps of the metastatic cascade could become new therapy targets. Conventional empirically derived treatment modalities should become flanked by methods aimed more specifically at critical steps of cancer spread in order to prevent progression of the disease. This is where basic research on mechanisms could make significant contributions to therapy planning in the future. Furthermore, possible negative effects of surgery, radiotherapy, and adjuvant chemotherapy or immunotherapy that could result in enhancement of metastatic progression need to be critically evaluated to limit them as much as possible.(ABSTRACT TRUNCATED AT 400 WORDS)

Cancer metastasis: experimental approaches, theoretical concepts, and impacts for treatment strategies.

Surgery for Pulmonary Metastasis: A 20-Year Experience

An attempt is made to clarify some general concepts of hematogenous metastatic patterns in humans, by the use of autopsy data. The significance and problems associated with 'false negative' reports are assessed. By the use of metastatic efficiency indices in which the incidence of specific target organ involvement is related to organ blood-flow, 'seed-and-soil' effects are discriminated from the effects of differential cancer cell delivery. An analysis of autopsy data from cases with a history of colorectal carcinoma is used to illustrate the importance of metastasis from metastases in the genesis of hematogenous metastatic patterns in humans.

Comments on hematogenous metastatic patterns in humans as revealed by autopsy

Hematogenous metastasis is a major consideration in the staging, treatment and prognosis of patients with cancer. Key events affecting hematogeneous metastasis occur in the microvasculature. This is a brief, selective review of some interactions involving cancer cells and the microvasculature in pathologic sequence, specifically: (1) intravasation of cancer cells; (2) the arrest of circulating cancer cells in the microvasculature; (3) cancer cell trauma associated with arrest; (4) microvascular trauma; (5) the inflammatory; and (6) the hemostatic coagulative responses associated with arrest, and finally (7) angiogenesis, leading to tumor vascularization. The evidence shows that through a series of complex interactions with cancer cells, the microvasculature acts as a rate-regulator for the metastatic process, in addition to providing routes for cancer cell dissemination and arrest sites for cancer cell emboli.

Interactions between cancer cells and the microvasculature: a rate-regulator for metastasis.

Following the injection of B16 melanoma cells into the portal veins of mice, all animals developed liver tumors, but only 16% developed lung tumors Portal vein injections of radiolabelled B16 and Walker 256 cancer cells into mice and rats, respectively, revealed that all of the cells were temporarily arrested in the liver and most were then slowly released Bioassays indicated that of 8 X 10(4) B16 cells released from the liver over 24 h after portal vein injections of 10(5) cells, only approximately 1% were delivered to the lungs in a viable state Experiments made with radiolabelled B16 cells showed that transit through either the liver or lungs following portal vein or tail vein injections, respectively, resulted in massive death of cancer cells It is suggested that the death of most circulating cancer cells passing through the first organ encountered after leaving their primary tumor, serves to severely limit their further direct spread to other organs It is therefore expected that metastases to these other organs would, to a large extent, be generated by cancer cells from metastases in the "first organs" as distinct from direct seeding from cancer cells released from the primary tumor If the results of the present experiments have general application, they serve to emphasize the importance of metastasis of metastases in the natural history of the spread of cancer In a previous publication (Weiss, 1980), studies of lung-to-liver traffic of cancer cells in rats revealed that, after tail vein injections, most Walker 256 cells were temporarily arrested in the pulmonary vasculature and then slowly released A large proportion of the released cancer cells were dead or lethally injured on release from the lungs, and this "first organ processing" apparently accounted for the comparative rarity of extrapulmonary tumors following tail vein injections In this communication, the concept of "first organ processing" of circulating cancer cells is further examined with respect to the liver-to-lung traffic of B16 melanoma and Walker 256 cells injected into the portal veins of mice or rats respectively Both of these cell types grow well in the lungs following tail-vein injection

Janet C. Holmes

Papers

Liver-to-lung traffic of cancer cells.