Aleksander Sochanik

Introduction of murine Il-4 gene into B16(F10) melanoma tumors by direct gene transfer with DNA-liposome complexes

Il-4 is a highly pleiotropic cytokine which induces cytotoxic activity when present at the tumor site. Death of tumor cells probably depends on the appearance of an inflammatory infiltrate composed of eosinophils and macrophages. Regression of established tumor masses has been readily observed upon direct intratumor implantation of cells which constitutively produce high amounts of Il-4. We now report a similar potent anti-tumor effect achieved via direct gene transfer, i.e. by injecting Il-4 DNA complexed with cationic liposomes into B16(F10) melanoma tumor in vivo.

A new cholesterol derivative suitable for transfecting certain type of cells in the presence of 10% serum

We developed a new cationic lipid suitable for use as a DNA carrier in the presence of 10% sera. The novel compound (abbreviated as Arg-Chol) contains cholesterol and a dipeptide consisting of glycine and sterically protected arginine. The efficiency of reporter gene transfection using liposomes based on this new reagent was compared with that of liposomes made with other cationic derivatives of cholesterol. Lipoplexes formulated with the newly synthesized lipid mediate in vitro transfection of B16(F10) murine melanoma cells in the presence of 10% sera more efficiently than in other cell lines and compared with other cholesterol derivatives studied.

Can inhibition of angiogenesis and stimulation of immune response be combined into a more effective antitumor therapy

Cancer initiation and progression is strongly influenced by the tumor microenvironment consisting of various types of host cells (inflammatory cells, vascular cells and fibroblasts), extracellular matrix and non-matrix molecules. Host cells play a defining role in two major processes crucial for tumor growth: angiogenesis and escape from immune surveillance. The interdependence of these processes resemble the principles of Yin and Yang, as the stimulation of tumor angiogenesis inhibits effective immune responses, while angiogenesis inhibition may have the opposite effect. These considerations may be useful in developing anticancer strategies based on the potentially synergistic combinations of antiangiogenic and immunostimulatory drugs.

Evolving models of tumor origin and progression

History of cancer disease models clearly illustrates the evolving nature of these concepts. Since such models undergo continual revisions and additions as a result of underlying medical research, they also tend to reorganize knowledge and allow perceiving previously unseen relationships. Growth of medical thought has been influenced for many centuries by an ancient Hippocratic concept of disease seen as a disturbance in bodily “humors.” True mechanisms of cell and tissue injury started to be elucidated only with the advent of postmortem pathological findings. Concerning cancer, when first disease-producing bacteria were identified in the nineteenth century, also neoplasms were treated as infectious diseases. Foreign organisms were thought to be present inside tumors. However, this hypothesis could not be confirmed by microscopic or histochemical studies. The latter suggested, instead, that tumors were rather formed by abnormal cells. Cancer was then started to be regarded as a disease of cells. This interpretation was radically altered by later developments in genetics which suggested that neoplasms can be treated as genetic diseases as pathologic cellular lesions are caused by mutations in specific genes. More recent models have compared carcinogenesis to evolutionary processes. Due to genetic instability, successive mutations, appearing in cells, lead to selection of cancer cells which feature specific phenotypic traits. The newest data indicate that there may be also a link between cancer and mutated stem cells. The review discusses main concepts of tumor origin forwarded since the beginnings of the nineteenth century.

Polarization of Tumor Milieu: Therapeutic Implications

During neoplastic progression, cancer cells recruit inflammatory cells (monocytes, neutrophils, mast, and dendritic cells, etc.), which become “educated” under the influence of factors released by cancer cells (mainly cytokines). As a consequence, the former lose their ability to present antigens. Instead, they become cells involved in remodeling of extracellular matrix and stimulate the formation of blood vessels (angiogenesis). Proangiogenic factors released by inflammatory cells act as immunosuppressants and the tumor milieu becomes proangiogenic and immunosuppressive. Latest studies have demonstrated the possibility of reverting such proangiogenic/immunosuppressive microenvironment which inhibits tumor growth. Reverted tumor microenvironment becomes anti-angiogenic and immunostimulatory. Reversal of tumor microenvironment is especially feasible with combinations of anti-angiogenic and immunomodulatory factors. For instance, combinations of VEGF, VEGFR2, or TGF-β activity inhibitors with immunostimulants such as anticancer vaccines, CpG sequences, or IL-12 were effective in inhibiting growth of experimental tumors. In our hands, a DNA vaccine directed against endoglin (CD105), a tumor vascular endothelial cell-surface protein, when combined with IL-12, led to a ca. 30 % cure rate in mice bearing experimental melanoma tumors. It appears that attempts to therapeutically revert tumor microenvironment might merit further consideration.