New Insights into Therapy-Induced Progression of Cancer

Abstract

The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.

Keywords: EMT; autophagy; cancer progression; cell cycle; chemoresistance; chemotherapy; intercellular communication; tumor microenvironment.

Figure 1

Acquisition of cancer cell resistance from the population point of view. The tumor is heterogeneous and consists of both therapy-sensitive and resistant cancer cells. Also, tumor-associated immune and stromal cells surround the tumor, creating a unique tumor microenvironment. Therapy simultaneously triggers many events: cell death, the transition to a state of senescence, the survival of pre-existing resistant clones, and the acquisition of new genetic and epigenetic features by cells, as well as activation of stress response cascades therein. All these processes lead not only to a change in the cellular composition of the tumor and tumor stroma but also to the transformation of the secretion profiles of all participants in intercellular communication. Such communication enhances the efficiency of the cellular response to stress, which, together with genomic instability and clonal selection, ensures the adaptation of cells to therapy, expansion of the most resistant tumor populations, and tumor recurrence.

Figure 2

The role of the therapy-induced intra- and intercellular events in the acquisition of cancer cell resistance. Stress caused by anticancer therapy triggers many events (acquisition of new mutations, changes in the regulation of the cell cycle, EMT, autophagy) which then leads to avoidance of cell death and a change in the efficiency of absorption/activation of the chemotherapy drug. In addition to intracellular signals, molecules from stromal cells, as well as other tumor cells, entering the cell from outside are involved in the induction of these events. Molecules of therapy-induced secretomes are marked by asterisks; molecules secreted from cancer cells are marked in black; molecules secreted from stromal cells are marked in blue.

Figure 3

The success of combined therapy depends on the cell cycle. The use of chemotherapeutic drugs that depend on the phase of the cell cycle and cause its arrest may lead to both higher and lower effectiveness of the combined therapy. Arresting the cell cycle in a phase corresponding to the maximum effectiveness of the second drug prolongs its time of action. Arresting the cell cycle in a phase preceding the action of the second drug impairs its effects. A, B, C, and D represent 4 phases of the cell cycle.

Figure 4

Features of tumor intercellular communication in response to therapy. During therapy, most of the sensitive tumor cells die, which leads to a decrease of their fraction in the tumor population and an increase in the proportion of resistant clones. Similarly, the composition of the total cell secretome and, consequently, its ability to participate in the process of acquiring therapy resistance change. Moreover, tumor cells dying under the effect of therapy release a number of molecules into the extracellular space which can induce the acquisition of resistance in untreated tumor cells.