The great escape: How metastases of melanoma, and other carcinomas, avoid elimination

Abstract

Cancer mortality ensues from metastatic growths. Cancers use two strategies to allow for this unrelenting expansion. The first way is that early metastases are often cryptic or dormant, being invisible to both innate suppressive actions and undetected clinically. Second, both the micrometastases and later clinically lethal growths are resistant to therapies, whether standard chemotherapies, targeted biologics, or even immunotherapies. These two modes of resistance necessitate new approaches to treatments if we are to eliminate mortality from solid tumors. However, to develop such therapeutic strategies, we first need to better understand the cellular behaviors and molecular events that enable the resistances. Herein, we present a comprehensive model of changing methods of avoidance and resistance that occur during tumor progression, and doubly confound treatment by mixing survival strategies throughout the continuum creating moving targets. Melanoma is presented as the model cancer, as it is being targeted by all three types of agents for disseminated disease, with breast and prostate cancer as two other key carcinomas. Impact statement Cancers kill mainly because metastatic disease is resistant to systemic therapies. It was hoped that newer targeted and immunomodulatory interventions could overcome these issues. However, recent findings point to a generalized resistance to elimination imparted by both cancer-intrinsic and -extrinsic changes to provide survival advantages to the disseminated tumor cells. Here, we present a novel conceptual framework for the microenvironmental inputs and changes that contribute to this generalized therapeutic resistance. In addition we address the issues of experimental systems in terms of studying this phenomenon with their advantages and limitations. This is meant to spur studies into this critical aspect of tumor progression that directly leads to cancer mortality.

A Perspective on Therapeutic Pan-Resistance in Metastatic Cancer

“…While cEMT is considered essential for successful tumor cell migration and invasion, it is now well accepted that cMErT confers increased survival and aids in successful colonization of metastatic sites by cancer cells [ 1 ]. Within this context, E-cadherin, a calcium-dependent cell-cell adhesion protein traditionally viewed as a tumor suppressor, seems to have a powerful role in therapeutic pan-resistance of micrometastases.…”

“…Despite the major advances in cancer treatment in recent decades, most of the progress has been achieved through early diagnosis and treatment of pre-metastatic cancer. Unfortunately, metastatic disease remains essentially incurable for most cancers, as metastases are not amenable to removal due to wide dissemination, exhibit intrinsic generalized resistance to chemotherapy and immunotherapy, and rapidly develop acquired resistance to targeted therapy via adaptive mutations [ 1 ]. It is imperative to understand the biology of this generalized resistance in order to translate this understanding into novel therapeutic approaches that will improve patient outcomes.…”

Adult Stem Cell Functioning in the Tumor Micro-Environment

“…Tumor dissemination from the prostate results from a metastatic cascade that involves a series of phenotypic switches. This progression is described in detail in other publications (examples of which include [1,4,8,45]). In brief, a subset of the carcinoma cells undergo a cancer-associated epithelial to mesenchymal transition (cEMT) to separate from the primary tumor and intravasate into circulatory conduits (lymph and blood vessels).…”

“…Upon dissemination, tumor cells step through two situations [1,2,3]. First, the cells must adapt to their new, hostile ectopic environment by undergoing a phenotypic shift that can lead to an extended period of dormancy, which is able to last for years to even decades; during this time the cells are resistant to death signals and chemotherapies and are invisible to the immune system [4]. During the second stage, these cryptic micrometastases emerge and outgrow as aggressive and lethal metastases.…”

“…During the second stage, these cryptic micrometastases emerge and outgrow as aggressive and lethal metastases. Unfortunately, these enlarging tumors acquire new modes of generalized resistance to killing, even if they do now express targets of newer immunomodulatory therapies [4]. To eliminate the mortality related to metastases, we need to keep the early metastases dormant, re-sensitize these growths to therapies, or develop new approaches.…”