tumor dissemination is a VERY early event (before tumor evident)--implications for

[Lani]

detection/treatment

As you know I have advocated early and repeated bone marrow testing (CTCs so far haven't proven to be as accurate--would be even better, easier on patients if they were). It seems the cells which end up killing patients are the ones that are waiting in dormancy to reawaken and multiply.

Strengthening the immune system cells which keep the isolated/disseminated tumor cells dormant should obviously be one goal of treatment--making breast cancer a disease one has to keep taking medications/vaccinations for--with eradication of these cells (by agents specific for cancer stem cells) being the ultimate goal ie, cure

Tumor cell spread: an early event kept in check by the immune system
[Eureka News Service]

The major cause of death in patients with cancer is the formation of tumors at sites distant to the initial tumor. Understanding more about the processes involved in the spread and development of tumors at distant sites is therefore of great importance for developing new anticancer therapeutics. A team of researchers, led by Jean-Pierre Abastado, at the Singapore Immunology Network, Singapore, has now provided insight into the issue by studying tumor cell dissemination in a mouse model of spontaneous melanoma (the most dangerous form of skin cancer). Martin Röcken, at Eberhard Karls University, Germany, discusses the importance of these data in an accompanying commentary.

The classical model of tumor cell dissemination is that it occurs late in tumor development, after the original tumor has grown. However, recent evidence suggests that single tumor cells spread to distant sites very early in the development of the original tumor. In the study, Abastado and colleagues found that tumor cells did spread to distant sites early during the development of the original tumor, even before it became clinically detectable. Interestingly, the disseminated tumor cells remained dormant for varying periods of time depending on the tissue to which they had spread. The reason the disseminated tumor cells remained dormant was that they were prevented from proliferating by immune cells known as CD8+ T cells. The authors therefore suggest that therapeutic approaches designed to bolster these immune responses should help prevent the outgrowth of tumor cells at distant sites and improve outcomes for individuals with early-stage cancer.

OPEN ACCESS: Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma
[Journal of Clinical Investigation]

Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8+ T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients.

OPEN ACCESS: COMMENTARY: Early tumor dissemination, but late metastasis: insights into tumor dormancy
[Journal of Clinical Investigation]

The classical model of metastasis is that tumor cell dissemination occurs late in tumor development, after the primary tumor has grown, and that only then will tumor cells invade the local tissue, enter the blood or lymphatic vessels, and colonize new sites to cause metastases. However, evidence increasingly indicates that single tumor cells spread to distant sites much earlier than previously believed. In this issue of the JCI, Eyles and colleagues provide new insight into the mechanisms underlying early tumor cell dissemination, formation of metastases, and tumor immunosurveillance using transgenic mice that spontaneously develop melanomas of the uvea. The authors provide striking evidence that tumor cells start to disseminate during the initial steps of tumor development, that late appearing metastases arise from these early disseminated tumor cells, and that CD8+ T cells inhibit the growth of disseminated tumor cells, surprisingly, not by cytotoxic effects, but through cytostatic effects.