Embracing cancer complexity: Hallmarks of systemic disease

Abstract

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.

Figure 1.. The “clouds of complexity” impinging on the frontiers of cancer biology and cancer medicine

Although the hallmarks of cancer have provided an overarching conceptual rationale for the myriad manifestations encompassing cancer as a disease, below this simplicity lies a dizzying diversity in mechanistic effects and phenotypes, both inside tumors and system-wide in the affected individual. Thus, above the horizon are clouds of complexity that, we argue in this perspective, are important and incompletely understood. Below the horizon lie mechanistic effectors—the building blocks of cancer—governing the inception and progression of cancer, which are also incompletely understood. Elucidating both dimensions of cancer as a systemic disease will be instrumental for ground-breaking innovations in prevention and enduring treatment of human cancer.

Figure 2.. The interplay between cancer driver mutations and environmental or endogenous tumor promoters in cancer risk

Mutations are essential for cancers to develop and may arise as a result of spontaneous errors in normal DNA replication, during aging of quiescent cells, or by exposure to mutagens in the environment. Obesity, dietary factors, and inflammation may also contribute to mutation burden indirectly, for example, through generation of reactive oxygen species (ROS), but this is unlikely to make a major contribution to overall mutation numbers. Mutations may remain dormant in normal tissues for long periods, unless the tissue is repeatedly exposed to an inducer of inflammation or tissue wounding, causing selection of cells carrying specific mutations, leading to clonal outgrowth. The particular mutations selected depend on many factors including the tissue or cell of origin, the host genetic background, or the nature of the specific promoting factor. Known or suspected exogenous promoting factors are shown as examples, as are potential endogenous or lifestyle-associated promoting factors.

Figure 3.. Tumor micro- and macro-environments

Representation of the complex tumor ecosystem. Interactions between diverse components of the tumor micro- and macro-environments are depicted, involving influences of the host, as well as external factors, on tumor growth and metastatic dissemination.

Figure 4.. Local and systemic drivers of protumorigenic myeloid dysregulation

(1) Molecules produced during tumor initiation that contribute to the recruitment and activation of macrophages that play a key role in the initiation of the inflammatory cascade and the release of inflammatory molecules in the blood circulation. (2) Release of inflammatory molecules in the blood circulation that drives the enhancement and dysregulation of myelopoiesis. (3) Epigenetic remodeling of myeloid progenitors in the bone marrow that contributes to the induction of nodes of molecular suppressive programs along the myeloid lineage. (4) Additional drivers produced in the local tumor microenvironment that contribute to further enhancement of myeloid suppression that further dampen antitumor immunity and promote tumor proliferation and growth. The list of molecules provided in each category is not exhaustive and is only provided as examples.

Figure 5.. Cancer as a systemic disease

Reciprocal relationships between cancer cell metabolism, the metabolism of heterotypic cells of the tumor microenvironment, and systemic metabolism. These metabolic crosstalks modulate cancer progression and could lead to cancer-associated cachexia. Detecting these metabolic alterations provides clinical opportunities for early detection and disease monitoring.

Figure 6.. Thromboinflammation and cancer

The interplay between the coagulation and innate immunity systems plays important roles throughout the development and growth of a tumor. Early interactions between neutrophils and tumor cells, including neutrophil-extracellular traps (NETs) produced by neutrophils, promote dormant tumor cell awakening, tumor survival and immune escape. Later aggregations between platelets and tumor cells promote tumor survival intravascularly and tumor spread. Activation of coagulation through tumor-specific mechanisms, such as the release of tissue factor, increases the risk of cancer-associated thrombosis.