Properties of bcr-abl-transformed mouse 12B1 cells secreting interleukin-2 and granulocyte-macrophage colony stimulating factor (GM-CSF): II. Adverse effects of GM-CSF

Abstract

Abstract. Granulocyte-macrophage colony stimulating factor (GM-CSF) is considered to be the most effective immunostimulating factor for the construction of gene-engineered anti-cancer vaccines. In some tumour cells, this type of genetic modification has resulted in the loss of the oncogenic potential. This was not the case with bcr-abl-transformed mouse 12B1 cells. A cell line, designated 12B1/GM-CSF/cl-5 producing more than 100 ng/10 6 cells/24 h, displayed higher pathogenicity than the parental, non-transduced cells. Although the tumours induced by the parental 12B1 cells and 12B1/GM-CSF/ cl-5 cells appeared nearly at the same time and then grew at an approximately equal rate, the latter mice were in a much poorer clinical condition. In these animals the growth of the tumours was associated with gradually increasing blood levels of GM-CSF. In both groups of animals splenomegaly was observed; it was much more pronounced in the case of 12B1/ GM-CSF/cl-5-inoculated animals. While in the case of animals inoculated with the parental cells the splenomegaly was probably mainly due to infiltration with tumour cells, in the animals inoculated with the GM-CSF-secreting cells splenomegaly and derangement of parenchymal organs, such as lungs, liver and kidneys, were more complex, including congestion and infiltration with hemopoietic cells, predominantly immature cells of myeloid lineage. The most conspicuous of these changes was the hyperaemia of the lungs. No such alterations were seen in animals inoculated with the parental cells. On the other hand, the contents of T regulatory cells were comparable in both groups and they increased in parallel at the end of the observation period. When GM-CSF neutralizing antibody was administered to animals inoculated with the 12B1/GM-CSF/ cl-5 cells, the pathological changes observed within the organs were suppressed, this proving that the overproduced GM-CSF and not any other substance, played the key role in their induction.

Integrative genomic analyses of a novel cytokine, interleukin-34 and its potential role in cancer prediction

“…There is evidence indicating that the M-CSF-IL-34-c-FMS axis is involved in the initiation, growth and metastasis of tumors ( 10 , 11 ). M-CSF levels may constitute a useful biomarker for a number of types of cancer, as it is expressed at high levels in a number of types of cancer, including breast cancer, ovarian cancer and colorectal carcinoma and its expression correlates with a poor prognosis ( 12 ). The direct inhibition of M-CSF or the inhibition of c-FMS kinase activity can lead to significant changes in the growth of grafted tumors (13.14).…”

“…Tumor-associated macrophages are the most abundant component of the leukocyte infiltrate of solid tumors. In M-CSF-deficient mice (M-CSF op/op or M-CSF −/− ), the growth of the primary tumor and the metastatic spread of tumor cells has been shown to be significantly reduced due to the inability of angiogenesis to feed the tumors ( 12 – 15 ).…”