Researchers have been studying metastasis for more than 100 years, and only recently have we gained insight into the mechanisms by which metastatic cells arise from primary tumours and the reasons that certain tumour types tend to metastasize to specific organs. Stephen Paget's 1889 proposal that metastasis depends on cross-talk between selected cancer cells (the 'seeds') and specific organ microenvironments (the 'soil') still holds forth today. It is now known that the potential of a tumour cell to metastasize depends on its interactions with the homeostatic factors that promote tumour-cell growth, survival, angiogenesis, invasion and metastasis. How has this field developed over the past century, and what major breakthroughs are most likely to lead to effective therapeutic approaches?

https://www.nature.com/articles/nrc1098.pdf?proof=t

The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited

A theoretical framework is proposed for the analysis of adhesion between cells or of cells to surfaces when the adhesion is mediated by reversible bonds between specific molecules such as antigen and antibody, lectin and carbohydrate, or enzyme and substrate. From a knowledge of the reaction rates for reactants in solution and of their diffusion constants both in solution and on membranes, it is possible to estimate reaction rates for membrane-bound reactants. Two models are developed for predicting the rate of bond formation between cells and are compared with experiments. The force required to separate two cells is shown to be greater than the expected electrical forces between cells, and of the same order of magnitude as the forces required to pull gangliosides and perhaps some integral membrane proteins out of the cell membrane.

https://science.sciencemag.org/content/sci/200/4342/618.full.pdf

Models for the specific adhesion of cells to cells

Metastases, rather than primary tumours, are responsible for most cancer deaths. To prevent these deaths, improved ways to treat metastatic disease are needed. Blood flow and other mechanical factors influence the delivery of cancer cells to specific organs, whereas molecular interactions between the cancer cells and the new organ influence the probability that the cells will grow there. Inhibition of the growth of metastases in secondary sites offers a promising approach for cancer therapy.

Dissemination and growth of cancer cells in metastatic sites

In this review the authors argue that the inhibition of cell death is an important characteristic of metastatic cancer cells. Will this view identify new treatments for metastatic disease?

Metastasis: a question of life or death

Singlet oxygen, a metastable state of normal triplet oxygen, has been identified as the cytotoxic agent that is probably responsible for in vitro inactivation of TA-3 mouse mammary carcinoma cells following incorporation of hematoporphyrin and exposure to red light. This photodynamic inactivation can be completely inhibited by intracellular 1,3-diphenylisobenzofuran. This very efficient singlet oxygen trap is not toxic to the cells nor does it absorb the light responsible for hematoporphyrin activation. We have found that the singlet oxygen-trapping product, o-dibenzoylbenzene, is formed nearly quantitatively intracellularly when both the furan and hematoporphyrin are present during illumination but not when only the furan is present during illumination. The protective effect against photodynamic inactivation of the TA-3 cells afforded by 1,3-diphenylisobenzofuran coupled with the nearly quantitative formation of the singlet oxygen-trapping product indicates that singlet oxygen is the probable agent responsible for toxicity in this system.

https://cancerres.aacrjournals.org/content/canres/36/7_Part_1/2326.full.pdf

Identification of singlet oxygen as the cytotoxic agent in photoinactivation of a murine tumor

Metastasis of cancer via the bloodstream is a major factor in the diagnosis, treatment, and prognosis of patients with cancer. Key events in hematogenous metastasis occur in the microvasculature. This is a brief, selective review of some interactions involving cancer cells and the microvasculature in pathological sequence, specifically: 1) intravasation of cancer cells; 2) the arrest of circulating cancer in the microvasculature; 3) cancer cell trauma associated with arrest; 4) microvascular trauma; 5) the inflammatory and 6) coagulative responses associated with arrest; and 7) the fate of arrested cancer cells. The evidence shows that in addition to providing routes for cancer cell dissemination and arrest sites for cancer cell emboli, the microvasculature, through a series of complex interactions with cancer cells, controls the efficiency of and acts as a rate regulator for the metastatic process.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.2.1.3275560

Interactions of cancer cells with the microvasculature during metastasis.

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

Principles of metastasis

Metastasis of cancer: a conceptual history from antiquity to the 1990s.

The deformability of the surface membranes of Sarcoma 37 and Ehrlich murine ascites tumor cells was assessed by the pressure required to suck a hemispherical bulge from these cells into a micropipette. It was shown that treatment with neuraminidase allowed the cells to be deformed with significantly less suction, and that enzymatic treatment also produced a significant reduction in surface charge as determined by measurement of cellular electrophoretic mobility. It is suggested that the increase in cellular deformability may be related to charge reduction, and that the charge at the cell periphery may affect not only the magnitude of the potential energy barriers hindering contact between cells, but also the ease with which cells can form low radius of curvature probes in order to help overcome these barriers.

/pdf/studies-on-cell-deformability-i-effect-of-surface-charge-2h166vckut.pdf

Leonard Weiss

Papers

Interactions of cancer cells with the microvasculature during metastasis.

Comments on hematogenous metastatic patterns in humans as revealed by autopsy

Principles of metastasis

Metastasis of cancer: a conceptual history from antiquity to the 1990s.

STUDIES ON CELL DEFORMABILITY : I. Effect of Surface Charge.