A review on targeting tumor microenvironment: The main paradigm shift in the mAb-based immunotherapy of solid tumors.

Monoclonal antibodies (mAbs) as biological macromolecules have been remarked the large and growing pipline of the pharmaceutical market and also the most promising tool in modern medicine for cancer therapy. These therapeutic entities, which consist of whole mAbs, armed mAbs (i.e., antibody-toxin conjugates, antibody-drug conjugates, and antibody-radionuclide conjugates), and antibody fragments, mostly target tumor cells. However, due to intrinsic heterogeneity of cancer diseases, tumor cells targeting mAb have been encountered with difficulties in their unpredictable efficacy as well as variability in remission and durable clinical benefits among cancer patients. To address these pitfalls, the area has undergone two major evolutions with the intent of minimizing anti-drug responses and addressing limitations experienced with tumor cell-targeted therapies. As a novel hallmark of cancer, the tumor microenvironment (TME) is becoming the great importance of attention to develop innovative strategies based on therapeutic mAbs. Here, we underscore innovative strategies targeting TME by mAbs which destroy tumor cells indirectly through targeting vasculature system (e.g., anti-angiogenesis), immune system modulation (i.e., stimulation, suppression, and depletion), the targeting and blocking of stroma-based growth signals (e.g., cancer-associated fibroblasts), and targeting cancer stem cells, as well as, their effector mechanisms, clinical uses, and relevant mechanisms of resistance.

Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation.

Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation.