Control dominating subclones for managing cancer progression and posttreatment recurrence by subclonal switchboard signal: implication for new therapies

Abstract

In contrast to hematological malignancies, meaningful improvements in survival statistics for patients with malignant brain tumors have not been realized in >40 years of clinical research. Clearly, a new medical approach to brain cancers is needed. Recent research has led to a new concept that needs to destroy all cancer subclones to control the cancer progression. However, this new concept fails to distinguish the difference between dominating subclones and dormant subclones. Here, we address the issue of clonal switch and emphasize that there may be one or more than one dominant clones within the tumor mass at any time. Destructing one dominant clone triggers activating other dormant subclones to become dominating subclones, causing cancer progress and post-treatment cancer recurrence. We postulate the concept of subclonal switchboard signaling and the pathway that involved in this process. In the context of stem cell and development, there is a parallel with the concept of quiescent/dormant cancer stem cells (CSC) and their progeny, the differentiated cancer cells; these 2 populations communicate and co-exist. The mechanism with which determines to extend self-renewal and expansion of CSC is needed to elucidate. We suggest eliminating the "dominating subclonal switchboard signals" that shift the dormant subclones to dominating subclones as a new strategy.

FIG. 1.

Subclonal switchboard signals (SSS) as mechanisms for leading to shift dominating subclones as triggered by environmental cues (stress) for cancer progression and post-treatment. A cancer subclone may gain a mutation that, in the appropriate environment cue, leads to dominating subclonal activation due to positive selection. Showed lettering and lines/arrows in black color is the current concept of treatment strategy for cancer-dominant subclonal cells (cancer stem cells) that may acquire a mutation, in the suitable environment, triggering to dominating subclonal expansion and growth. When this dominating subclone is specifically destroyed, it sends out dominating subclonal-SSS to a dormant/quiescent subclonal cell, which gets activated for dominating subclonal expansion and growth.

FIG. 2.

Blockade of the dominating subclonal SSS as a new therapeutic strategy to suppress the dominating subclone shift to control cancer progression and post-treatment cancer recurrence. Showed is the proposed new treatment paradigm that should target the subclonal-SSS. Blocking the dominating subclonal SSS leads to subclonal quiescence, so keeping tumors alive but small and manageable (dormant/quiescent subclone).