Targeting the duality of cancer

Abstract

Cancer is the second leading cause of death in the United States, and is an increasing cause of death in the developing world. While there is great heterogeneity in the anatomic site and mutations involved in human cancer, there are common features, including immortal growth, angiogenesis, apoptosis evasion, and other features, that are common to most if not all cancers. However, new features of human cancers have been found as a result of clinical use of novel "targeted therapies," angiogenesis inhibitors, and immunotherapies, including checkpoint inhibitors. These findings indicate that cancer is a moving target, which can change signaling and metabolic features based upon the therapies offered. It is well-known that there is significant heterogeneity within a tumor and it is possible that treatment might reduce the heterogeneity as a tumor adapts to therapy and, thus, a tumor might be synchronized, even if there is no major clinical response. Understanding this concept is important, as concurrent and sequential therapies might lead to improved tumor responses and cures. We posit that the repertoire of tumor responses is both predictable and limited, thus giving hope that eventually we can be more effective against solid tumors. Currently, among solid tumors, we observe a response of 1/3 of tumors to immunotherapy, perhaps less to angiogenesis inhibition, a varied response to targeted therapies, with relapse and resistance being the rule, and a large fraction being insensitive to all of these therapies, thus requiring the older therapies of chemotherapy, surgery, and radiation. Tumor phenotypes can be seen as a continuum between binary extremes, which will be discussed further. The biology of cancer is undoubtedly more complex than duality, but thinking of cancer as a duality may help scientists and oncologists discover optimal treatments that can be given either simultaneously or sequentially.

Fig. 1

Potential outcomes in patients with melanoma undergoing sentinel lymph node biopsy, demonstrating hematogenous and lymphatic metastasis. Acknowledgement and credit to Brian C. Brockway, M.S., Medical Media, Atlanta VA Medical Center

Fig. 2

Signaling in primary tumor and metastasis based upon mitochondrial bioenergetic profile. Large primary tumors express high levels of PCG1α in a component of their cells. Respiratory cells have both motile and non-motile components. Non-motile components have increased susceptibility to chemotherapy and radiation and represent, in part, the initial population that responds to chemotherapy and radiation. After maximal response, a glycolytic slow growing population is left behind, as well as motile respiratory cells that give rise to metastasis. These metastatic cells may maintain respiration through elevated levels of ClpXP. Once metastatic cells reach a niche, they can reform a mixed population of respiratory and glycolytic cells. Acknowledgement and credit to Brian C. Brockway, M.S., Medical Media, Atlanta VA Medical Center

Fig. 3

The source and location of reactive oxygen plays a dualistic role in tumor cells. NADPH oxidases are tethered to the cellular membrane in part by Akt. These complexes generate superoxide that oxidizes redox-sensitive sulfhydryl groups in the cytoplasm. This leads to inactivation of cellular phosphatases, activation of cellular kinases, and polymerization of F-actin, allowing motility. In contrast, mitochondrial-derived reactive oxygen may be a highly pro-apoptotic mechanism, leading to VDAC channel formation, loss of mitochondrial potential and, thus, loss of ATP. Fusion mitochondria may be highly susceptible to these events, while fission mitochondria may be less susceptible to these events, and fission may serve as a defense mechanism against mitochondrial reactive oxygen. Acknowledgement and credit to Brian C. Brockway, M.S., Medical Media, Atlanta VA Medical Center