Liotta et al. hypothesized that the relative cellular abundance of tens of thousands of different proteins, along with their cleaved or modified forms, is a reflection of ongoing physiological and pathological events. They further postulate that as tissues are perfused by blood and lymph, proteins and protein fragments, passively or actively, enter the circulation. Thus, the complex chemistry of the tumor-host microenvironment should generate unique signatures in the blood microenvironment. I agree with this statement. The major question here is if these putative proteomic changes in the blood can be captured by the SELDI-TOF technology, as applied in the published papers. In my opinion, it is highly unlikely that a small and localized tumor will be able to modify the serum proteomic pattern to a degree that can be recognized by the SELDI-TOF technique. As I will further elaborate later, SELDI-TOF, and other proteomic technologies based on mass spectrometry, may not be sensitive enough to detect the low-abundance "signature" molecules that are released by a few tumor cells or their microenvironment into the circulation. I do believe that informative molecules originating from tumor cells or their microenvironment may indeed be present in biological fluids and that their identification may lead to the discovery of potential new biomarkers.
The identification of these molecules will likely require ultrasensitive techniques capable of measuring concentration ranges 10-12 mol/liter or lower (far lower than those achieved by current SELDI-TOF protocols, see below).
An alternative hypothesis for the observed differences in proteomic patterns in serum between normal individuals and cancer patients may be the detection of high-abundance molecules that are not produced by the tumor cells but rather represent epiphenomena of tumor presence. For example, it has been postulated by this author that at least some of the detected molecules represent acute-phase reactants that are released into the circulation by the liver and other organs (36, 37). It has been shown as early as 30–40 years ago that such molecules are not specific for the presence of any cancer, and for this reason they have not been used in clinical practice for cancer diagnosis or monitoring, although their concentrations may be elevated in serum of some cancer patients (38).