Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, is a first-line treatment for metastatic renal cell carcinoma (mRCC) in patients in ‘low’ and ‘intermediate’ Memorial Sloan Kettering Cancer Center and Heng risk groups. Disruptions of hematopoiesis, such as anemia, neutropenia, and thrombocytopenia, are typically observed during sunitinib treatment. When it comes to RBC parameters, an increase in mean cell volume (MCV) tends to occur, meeting the criteria for macrocytosis in some patients (MCV > 100 fL). We examined changes in RBC parameters of 27 mRCC patients treated with sunitinib (initial dose of 50 mg/day, 6-week treatment: 4 weeks on, 2 weeks off) and correlated them with progression-free survival time (PFS). Patients who had macrocytosis after 3 treatment cycles had significantly longer PFS than those whose MCV stayed less than 100 fL (not reached vs. 11.2 months, p < 0.001). We also found a correlation between MCV values after the first and third treatment cycles and the risk of progression: HR of 0.9 (0.81–0.99) and 0.76 (0.65–0.90) per 1 fL increase in MCV, respectively. The mechanism of MCV elevation during sunitinib treatment has not yet been fully explained. One of the probable causes is sunitinib’s inhibitory influence on c-Kit kinase, as is the case with imatinib. For mRCC patients, this phenomenon could help predict PFS, but since our sample was small, further studies are essential

Chronic VEGF Blockade Worsens Glomerular Injury in the Remnant Kidney Model

VEGF inhibition can promote renal vascular and parenchymal injury, causing proteinuria, hypertension and thrombotic microangiopathy. The mechanisms underlying these side effects are unclear. We investigated the renal effects of the administration, during 45 days, of sunitinib (Su), a VEGF receptor inhibitor, to rats with 5/6 renal ablation (Nx). Adult male Munich-Wistar rats were distributed among groups S+V, sham-operated rats receiving vehicle only; S+Su, S rats given Su, 4 mg/kg/day; Nx+V, Nx rats receiving V; and Nx+Su, Nx rats receiving Su. Su caused no change in Group S. Seven and 45 days after renal ablation, renal cortical interstitium was expanded, in association with rarefaction of peritubular capillaries. Su did not worsen hypertension, proteinuria or interstitial expansion, nor did it affect capillary rarefaction, suggesting little angiogenic activity in this model. Nx animals exhibited glomerulosclerosis (GS), which was aggravated by Su. This effect could not be explained by podocyte damage, nor could it be ascribed to tuft hypertrophy or hyperplasia. GS may have derived from organization of capillary microthrombi, frequently observed in Group Nx+Su. Treatment with Su did not reduce the fractional glomerular endothelial area, suggesting functional rather than structural cell injury. Chronic VEGF inhibition has little effect on normal rats, but can affect glomerular endothelium when renal damage is already present

Mesenchymal Stem Cells During Tumor Formation and Dissemination

The tumor microenvironment (TME) is composed by malignant and non-malignant cells, all embedded in a dense extracellular matrix (ECM) rich with unstable vessels. Targeting TME components, especially those associated with the vasculature such as endothelial cells (ECs) and pericytes, has shown clinical benefits. The identity correlation between pericytes and mesenchymal stem cells (MSC) has broadened the functional roles of these adult stem cells, now tightly involved in cancer biology. This review summarizes this involvement, focusing on their participation in: 1) skeletal primary malignancies; 2) formation of distant primary tumors; 3) intravasation of cancer cells at the primary tumors; and 4) extravasation of cancer cells at the target organ. Given their tropism to sites of injury and inflammation, bone marrow (BM)-derived MSC (BM-MSC) follow tumor-derived signals and participate in the formation of distant primary tumors, by repopulating their perivascular habitat and contributing to tumor growth. Thus, targeting primary tumor’s pericytes severely reduces growth, yet dissemination of constitutive cancer cells increases. The impact of pericyte-deficient coverage on the target organ is rather opposite, generating a selective reduction of cancer cell invasion in some organs. These roles seem to be founded on the distinct molecular communication and physical interactions between MSC as pericytes and the cancer cells