HOW CANCER SPREADS - THE MYSTERIES OF METASTASIS

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HOW CANCER SPREADS - THE MYSTERIES OF METASTASIS

_http://www.cancerdecisions.com/100508.html_

(http://www.cancerdecisions.com/100508.html)

 

 

When cancer is localized to the site in which it originated, it can often be

controlled, and sometimes even cured, by conventional methods; but when

cancers metastasize - i.e., spread to distant locations - the situation becomes

considerably more ominous. The ability of cancer to metastasize is what makes

the disease potentially so deadly.

For the past several decades it has generally been assumed that metastatic

spread happens relatively late in the course of the disease, and that it

occurs largely as a result of increasing malignancy in the original (primary)

tumor

.. However, several recent papers, including one published last week in the

journal Science, have presented new evidence challenging this theory and

raising some very interesting questions about how and when cancers begin to

spread

(Podsypanina, 2008).

The Science paper, authored by researchers from the Department of Cancer

Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, showed

that, contrary to the late spread hypothesis, cells - even normal,

non-malignant cells - can, and apparently very frequently do, break away from

the organ

or tissue in which they originated, and take up residence in distant organs

and tissues. In other words, the phenomenon of cells breaking away and

traveling via the bloodstream and lymphatic vessels to other sites is neither

unusual nor is it by any means always a function of malignancy. Furthermore, the

researchers showed that such breakaway cells can survive for extended periods in

tissues other than those in which they originated. By contrast, in

experimental models of metastasis millions of tumor cells must be injected into

the

bloodstream in order to establish a very small number of metastatic tumors:

inducing metastasis is by no means simple.

Since clusters of cells break off primary tumors constantly, why do only

such a small number develop into secondary cancers? Why not all of them? What

enables a breakaway group of cells to become malignant? Why are some sites -

for example, the liver, lungs, brain and bones - more commonly affected than

others? While the anatomical layout of blood vessels or lymphatic drainage may

to some extent dictate the likely site of development of metastases, at least

30 percent of metastases arise in locations which are not close to, or linked

by direct blood supply to, the primary tumor. Neither are all tumors of the

same type equally likely to give rise to metastases. While one cancer may

rapidly spread far and wide another cancer of the same kind may take years to

spread, or not spread at all.

The prevailing 'late metastasis' theory suggests that the breakaway cells

arrive in their distant location already in a premalignant state - i.e., primed

and ready to develop into a satellite tumor. However, the 'early metastasis'

research described in the Science paper suggests that the migration of cells

to distant tissues is not in and of itself dangerous, and that the breakaway

cells arrive in their new location in a normal, not a malignant or

premalignant, state. Danger only arises when those breakaway cells, now residing

in

distant tissues, somehow become transformed genetically and begin to

proliferate.

This paradigm shift raises questions about the validity and relevance of

metastasis research which is based on cell lines drawn from advanced cancer

tissue. If breakaway cell colonies in distant tissues are not already

premalignant and do not carry the hallmark genetic flaws that are typical of

the primary

tumor, does it make sense to use obviously genetically abnormal tissue in

experimental metastasis research? Maybe not, say the authors of the Science

paper. It may also be prudent to rethink the assumption that metastatic lesions

will respond to treatment in exactly the same way as the primary tumor.

For several years now, Harvard researcher Michael Retsky and his colleagues

Romano Demicheli of the Istituto Nazionale Tumori, Milano, Italy, William

Hrushesky of the University of South Carolina, and Professor Michael Baum of

University College, London, have been publishing papers on their work with

breast cancer, showing that removal of the primary tumor may, in certain cases,

actually trigger the start of malignant transformation in dormant cell clusters

distant from the primary site. In a review paper published this week in

Annals of Oncology, they reiterate their central hypothesis, namely that while

surgical removal of a primary breast tumor may be curative (or at least

beneficial) for many patients, it may also hasten development of metastatic

tumors

for others (Demichelli, 2008). In other words, the primary tumor may act as a

brake on the growth of distant breakaway cells, and at least in some cases

the excision of the primary tumor may remove that restraint on growth, spurring

the malignant transformation of these distant satellites of previously

dormant tissue.

Perhaps it is time to rethink the currently prevailing theory of metastasis,

and to look more closely at the role of the primary tumor in controlling the

behavior of breakaway cells in distant sites.

 

 

 

--Ralph W. Moss, Ph.D.

 

References:

Demicheli R, Retsky MW, Hrushesky WJM, et al. The effects of surgery on

tumor growth: a century of investigations. Ann Oncol 2008 June 10.

Podyspanina K, Du YC, Jechlinger M, et al. Seeding and propagation of

untransformed mouse mammary cells in the lung. Science 2008;321(5897):1841-4.