Human mesenchymal stem cells increase LLC metastasis and stimulate or decelerate tumor development depending on injection method and cell amount.

Mesenchymal stem cells (MSCs) being injected into the body can stimulate or decelerate carcinogenesis. Here, the direction of influence of human placenta-derived MSCs (P-MSCs) on the Lewis lung carcinoma (LLC) tumor development and metastatic potential is investigated in C57BL/6 mice depending on the injection method. After intramuscular co-inoculation of LLC and P-MSCs (LLC + P-MSCs), the growth of primary tumor and angiogenesis are slowed down compared to the control LLC on the 15th day. This is explained by the fact of a decrease in the secretion of proangiogenic factors during in vitro co-cultivation of an equal amount of LLC and P-MSCs. When P-MSCs are intravenously (i.v.) injected in the mice with developing LLC (LLC + P-MSCs(i.v.)), the tumor growth and angiogenesis are stimulated on the 15th day. A highly activated secretion of proangiogenic factors by P-MSCs in a similar in vitro model can explain this. In both the models compared to the control on the 23rd day, there is no significant difference in the tumor growth, while angiogenesis remains correspondingly decelerated or stimulated. However, in both the models, the total volume and number of lung metastases constantly increase compared to the control: it is mainly due to small-size metastases for LLC + P-MSCs(i.v.) and larger ones for LLC + P-MSCs. The increase in the rate of LLC cell dissemination after the injection of P-MSCs is explained by the disordered polyploidy and chromosomal instability, leading to an increase in migration and invasion of cancer cells. After LLC + P-MSCs co-inoculation, the tumor cell karyotype has the most complex and heterogeneous chromosomal structure. These findings indicate a bidirectional effect of P-MSCs on the growth of LLC in the early periods after injection, depending on the injection method, and, correspondingly, the number of contacting cells. However, regardless of the injection method, P-MSCs are shown to increase LLC aggressiveness related to cancer-associated angiogenesis and metastasis activation in the long term.

Paraneoplastic syndrome in mice bearing high-angiogenic variant of Lewis lung carcinoma: relations with tumor derived VEGF.

BACKGROUND: It is well-known that tumor exerts nonmetastatic systemic effect on organism caused the development of paraneoplastic syndrome (PNS). Recent findings point to relationships between development of PNS and tumor-derived vascular endothelial growth factor (VEGF). AIM: Comparative study of PNS manifestations in mice with transplanted two variants of Lewis lung carcinoma with different angiogenic potential. METHODS: Plasma VEGF level was determined by immunoenzyme method, hematological indices were estimated with the use of hematological analyzer, the weight and cellularity of spleen and thymus were registered and histological analysis of tissue section of these organs was performed. RESULTS: Manifestations of anemia, extramedullary hemopoiesis and tumor-associated inflammatory disease was observed in animals with high angiogenic LLC/R9 variant and was not registered in low angiogenic LLC. The emergence of PNS symptoms correlated with elevated level of circulating VEGF at the early stages of LLC/R9 growth. CONCLUSION: Manifestation of the paraneoplastic hematological syndrome most likely is conditioned on the ability of cancer cell to secrete VEGF in a high rate.

Anticancer activity of aconitine-containing herbal extract BC1.

AIM: The objective of the study was the investigation of anticancer activity of aconitine-containing herbal extract BC1 against two tumor strains with different metastatic potency: strongly metastatic Lewis lung carcinoma (LLC) and its weakly metastatic counterpart (LLC-R9). RESULTS: It was shown that low proliferative activity and high metastatic potential of LLC correlated with high refractoriness of this tumor to BC1 action, while significant inhibition of tumor growth and metastasis by BC1 were observed against actively proliferating and weakly metastatic LLC-R9. Maximal antitumor activity of BC1 (> 70% of inhibition of primary tumor growth) and antimetastatic action (88% of metastatic inhibition) were observed at the dose of MTD/20. High efficacy of BC1 against LLC-R9 was shown to be accompanied by 2-fold increase of apoptosis rate predominantly in diploid cells. CONCLUSIONS: The obtained results showed the ability of aconitine-containing herbal extract BC1 to inhibit growth of primary tumor and metastases of actively proliferating and weakly metastatic variant of Lewis lung carcinoma.