Revisiting 'Hallmarks of Cancer' In Sarcomas

Abstract

There is no doubt that anyone who has participated in cancer care or research has once read the 'Hallmarks of Cancer' papers published by Hanahan and Weinberg in 2001 and 2011. They initially defined the six qualities of cancer cells as cancer hallmarks in 2001, but expanded that to 11 as a next generation in 2011. In their papers, they discussed the potential treatment strategies against cancer corresponding to each of the 11 hallmarks, and to date, proposed therapies that target genes and signaling pathways associated with each of these hallmarks have guided a trail that cancer treatments should take, some of which are now used as standard in clinical practice and some of which have yet to progress that far. Along with the recent advances in cancer research such as genomic analysis with next generation sequencing, they can be reconverged to an alternative six categories defined as selective proliferative advantages, altered stress response, deregulated cellular metabolism, immune modulation and inflammation, tumor microenvironment, tissue invasion and metastasis. In this paper, we will overview the current state of these alternative hallmarks and their corresponding treatments in the current sarcoma practice, then discuss the future direction of sarcoma treatment.

Keywords: cancer biology; hallmarks of cancer; precision medicine; sarcoma.

Figure 1

Reorganization of 11 hallmarks into 6 hallmarks by combining the hallmarks which share their roles in cancer evolution and progression. Sustained growth signal and evading anti-growth signal are combined into selective proliferative advantages; resisting programmed cell death and enabled replicative immortality and genome instability into altered stress response; tumor promoting inflammation and avoiding immune destruction into immune modulation, and tumor microenvironment including vascular structure reorganization such as angiogenesis, and the original hallmarks of deregulated cellular metabolism and tissue invasion and metastasis are maintained as they are.

Figure 2

Targeted signaling pathways in sarcomas. Most common targets take a place in receptor tyrosine kinases signaling and cell cycle regulators related with p53 and Rb pathways. Epigenetic regulators such as EZH2 could be the potential therapeutic targets in specific sarcomas.

Figure 3

Chromothripsis is a catastrophic single event which extensively results in DNA fragmentation. Certain portions of chromosomes are lost to the cells during the chromosomal repair and these mis-rearrangements progress towards cancer formation.

Figure 4

Chromoplexy occurs in a form of ruptures in multiple localized chromosomes at the same time in the nuclear transcription hub, which simultaneously regulates the expression of multiple genes on multiple chromosomes in close proximity, and in the process of repair, different chromosomes mistakenly fuse with each other, which is involved in carcinogenesis.

Figure 5

Main sources of cell energy are glycolysis and OXPHOS, but various metabolites involve the many aspects of cellular activities such as nucleotides generation, immune cell function.

Figure 6

The binding of checkpoint protein PD-L1on cancer cells to PD-1on T cells keeps T cells from killing tumor cells in check. Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells.

Figure 7

Additive effect of eribulin with irradiation has shown in advanced myxofibrosarcoma patient of our own case. Patient with axillary lymph node metastasis (LN mets, white arrow) who received concomitant administration of eribulin and irradiation onto LN mets showed the augmented effective with drastic shrinkage of tumor mass.: Treatment with eribulin alone allowed tumor enlargement after 4 months, then radiotherapy was added on eribulin (a to b), and tumor showed remarkable shrinkage after 6months of radiotherapy (b to c), then tumor shrinkage was maintained for more than 3 years with continuous eribulin treatment (c to d).

Figure 8

Growing evidence supports a collective route for invasion resulting in polyclonal metastasis and many collaborators like platelets, neutrophils and endothelial cells are involved in the metastatic cascade with numerous enzymes, growth factors and chemokines.

Figure 9

The summary of reorganized hallmarks and possible targetable factors are depicted. Number of targets are involved in signaling pathways downstream of growth factors, cytokines as well as stress responses.