ABSTRACT
M etastasis is defined as the transfer of cancer cells from the prim ary tum or of one organ, or part of it, to another not directly connected to it. Recent investigations have been dem onstrated that m etastasis is not a random process but a selective process w hich involves the release of cancer cells from the prim ary tumor, dis sem ination to distant sites, arrest in the m icrocirculation of organs, extravasation and infiltration into the strom a of those organs, and the survival and growth into new tum or foci, or m etastases. The outcom e of the m etastatic process depends on the balance of the interactions or interplays betw een cancer cell properties and the host factors or cell environm ental factors or the "m ilieu " of the new organ where the seeded cancer cells m ust grow and survive. A natom ical drainage is not the only reason for the location of m etastasis in specific organs. It has been noted, that m etastases derived from breast cancer appear in skeletal bones and have to by pass the lung, or the occurrence of prostate m etastases to the skull, or colon to brain, or of m elanom a to the lung m ake the idea of "seed and soil" hypothesis announced m ore than 100 years ago by Paget (1). A fter exam ination of several autopsy records of w om en w ho died of breast cancer, and the high frequency of m etastases in the ovaries or in the bones, he concluded that m etastasis occurred only w hen certain favored tum or cells (the "seed s") had a special affinity for the grow th m ilieu provided by certain specific organs (the "so il"). Thus, the form ation of m etastasis required the interaction of the right cells w ith com patible organ environm ent. In addition to the fact that m etastatic cancer cells although em erge from the prim ary cancer cells to w hom they share biological properties, the m etastatic cells are a different phenotype w ith m ore abnorm al and bizarre cell surface, clonal, im m unological and horm onal behavior, and they can have a clonal origin, and different m etastases can originate from the proliferation of d ifferent single cells; the m ost im portant principle for the design of new cancer therapies and developm ent of novel anticancer drugs, and that the outcom e of m etastasis depends on m ultip le in teractions, interp lay or "cross ta lk " of m etastatic cells w ith the hom eostatic m echanism s of the new cell environm ent w here the m etastatic cells m ust grow and survive. Changes in this cell environm ent, nam ely changes, alterations or aberrations in the cancer cell m etabolism can be a potential target and also a potential factor for the developm ent or inhibition of m etastatic cancer cells. It is well know n that m ost
cancer patients (approxim ately 60%) die by distant m etastases, and not by the grow th of prim ary tumor, as am ply docum ented by the five year survival data of patients w hose prim ary tum or has been surgically removed. Also, at the tim e of the initial treatm ent, m ost cancer patients have already clinically or m icroscopi cally detectable m etastases. H ence, there is an u rgen t need fo r better und ersta nd in g o f metabolic and m olecular m echanism s of the m etastatic process w hich can provide a biological foundation for the design of m ore effective therapy of m etastatic can cers as well as the developm ent of novel anticancer drugs that can circum vent or overcom e the m ultidrug resistance and spread of m etastatic cells (2-10).
