How is cancer complex?

Abstract

Cancer is typically spoken of as a “complex” disease. But, in what sense are cancers “complex”? Is there one sense, or several? What implications does this complexity have – both for how we study, and how we intervene upon cancers? The aim of this paper is first, to clarify the variety of senses in which cancer is spoken of as "complex" in the scientific literature, and second, to discover what explanatory and predictive roles such features play.

Glossary

Robustness

Sometimes used interchangeably with “resilience,” “robustness’ typically refers to the greater or lesser capacity of a cancer (both as a whole, or, particular cancer cells) to grow, survive and/or seed metastases, develop resistance to treatment, or to “resist attacks” from the immune system.

Heterogeneity

This typically refers to extent of genetic or genomic variability across or within particular types or subtypes of cancer (ranging from the sheer number of mutations, to varieties of types of mutations and chromosomal alterations – inversions, deletions, etc.), but may also refer to genomic variability within a population of cancer cells (“intra-tumor heterogeneity”: co-evolving lineages, or genetically diverse populations or subpopulations). “Heterogeneity” may (confusingly) also refer to diversity of parts, entities, or properties of entities that play a causal role in a cancer, such as: microRNA, epigenomic features (hyper- or hypo-methylation), or co-factors in the tissue microenvironment, such as fibroblasts, or leukocytes.

Network

A “network” typically refers to a relationship among signaling molecules or gene products, in ways that promote or halt various activity, or maintain or disrupt various functions. Thus, e.g., various products of oncogenes and tumour suppressors may be said to form networks or “pathways” involved in various processes (e.g., metastasis). A “complex regulatory network” may be a set of signaling proteins that modulates the expression of others, in service of some function (e.g., the epithelial-mesenchymal transition). Networks can span several spatiotempral levels, and stages of gene expression or modification of expression: e.g., including transcription, post-transcription, epigenetic modification, alternative splicing, protein stability and subcellular localization. Sometimes parts of networks are also referred to as “signaling cascades,” where some proteins (e.g., insulin-like growth factor (IGF)) promote the activity of others. Typically a “network” will involve some form of feedback, insofar as several tend to act together in service of maintaining or promoting function (or, in the case of cancer, malfunction).

Biomarker (Sometimes used to refer to instances of bearers of what Ladyman and Wiesner call “memory” or “information.”)

This may refer to any protein, gene variant, or other biological feature (RNA sequence variant) associated with a particular outcome of interest, such as responsiveness to a drug, or association with high mortality. Such markers can form parts of signaling cascades or networks.

Scale-free

This refers to a type of network organization where there are a few highly connected nodes. It is sometimes also referred to as a highly “modular” network.

Modularity

This is type of organization of a network with several nodes that are highly connected. Such nodes tend to play important regulatory roles in key functions in the cell, or may regulate or co-regulate several signaling pathways associated with such roles.

Feedback mechanisms

Pathways of regulating functions in the cell that have a “looped” organization, such that outputs of a pathway are “fed” back into that same pathway, carrying “information” about downstream effects. An example of “feedback” is, e.g., a double-negative feedback loop, which serves to maintain homeostasis (cf. Zhang & Weinberg, 2018).

Complexity

As discussed in Table 1, this term is used to refer to everything from genomic heterogeneity, to heterogeneity of many other parts and processes involved in cancer progression (mRNA, etc.), to functional pleiotropy, to organizational features of signaling pathways in the cell and across the cell and tissue microenvironment.

Adaptation

In the context of cancer research, the “adaptive” features of cancer cells (or, for that matter, whole tumors) are those that tend to promote either cell or tumor growth, invasiveness, or metastasis, or enable resistance, e.g., to chemotherapy. This may refer to “adaptation” in the sense of “plastic response to environment,” or adaptation in the sense of traits that have been effectively subject to selection over the course of the tumor’s progression.