Radical Tumor Denervation Activates Potent Local and Global Cancer Treatment

Abstract

This preliminary study seeks to determine the effect of R&P denervation on tumor growth and survival in immunocompetent rats bearing an aggressive and metastatic breast solid tumor. A novel microsurgical approach was applied “in situ”, aiming to induce R&P denervation through the division of every single nerve fiber connecting the host with the primary tumor via its complete detachment and re-attachment, by resecting and reconnecting its supplying artery and vein (anastomosis). This preparation, known as microsurgical graft or flap, is radically denervated by definition, but also effectively delays or even impedes the return of innervation for a significant period of time, thus creating a critical and therapeutic time window. Mammary adenocarcinoma cells (HH-16.cl4) were injected into immunocompetent Sprague Dawley adult rats. When the tumors reached a certain volume, the subjects entered the study. The primary tumor, including a substantial amount of peritumoral tissue, was surgically isolated on a dominant artery and vein, which was resected and reconnected using a surgical microscope (orthotopic tumor auto-transplantation). Intending to simulate metastasis, two or three tumors were simultaneously implanted and only one was treated, using the surgical technique described herein. Primary tumor regression was observed in all of the microsurgically treated subjects, associated with a potent systemic anticancer effect and prolonged survival. In stark contrast, the subjects received a close to identical surgical operation; however, with the intact neurovascular connection, they did not achieve the therapeutic result. Animals bearing multiple tumors and receiving the same treatment in only one tumor exhibited regression in both the “primary” and remote- untreated tumors at a clinically significant percentage, with regression occurring in more than half of the treated subjects. A novel therapeutic approach is presented, which induces the permanent regression of primary and, notably, remote tumors, as well as, evidently, the naturally occurring metastatic lesions, at a high rate. This strategy is aligned with the impetus that comes from the current translational research data, focusing on the abrogation of the neuro–tumoral interaction as an alternative treatment strategy. More data regarding the clinical significance of this are expected to come up from a pilot clinical trial that is ongoing.

The Crosstalk between Nerves and Cancer—A Poorly Understood Phenomenon and New Possibilities

“…There are different neutralizers or antibodies targeting the NGF pathway that have been tested in animals [33]. The surgical and pharmacologic tumor denervation of solid cancers resulted in the slowing or even stopping of cancer growth in mice [34]. The depletion of neurogenic niches in the brain by a racting neural progenitors support its own development might explain the cognitive impairment in cancer patie [1].…”

“…There are different neutralizers or antibodies targeting the NGF pathway that ha been tested in animals [33]. The surgical and pharmacologic tumor denervation of so cancers resulted in the slowing or even stopping of cancer growth in mice [34].…”

“…The therapeutic potential of denervation has been previously described. In a rat model of breast cancer, radical and persistent denervation resulted in cancer regression and long-term survival, whereas untreated rats died very quickly [34]. Magnon et al [58] investigated the effects of sympathectomy on prostate cancer in a mouse model.…”