Hallmarks of Cancer Flashcards
When speaking of cancer, define these:
Local or localized disease
Locally advanced or loco-regional disease
Distant or advanced
Local or localized disease: Cancer is confined to one organ or structure.
Locally advanced or loco-regional disease:
Cancer is metastatic to a local lymph node
and/or is locally invasive within the
surrounding tissues.
Distant or advanced: Cancer has metastasized beyond the local lymph node.
Tx modalities for canine tumor treatment. (5)
Advanced oncologic surgery
Multidrug chemo protocols
Radiotherapy
Immunotherapy
Target therapy with e.g. TKI:s (tyrosine kinase inhibitors)
Chemotherapies target cells in the in what phase?
Chemotherapies target cells in the G1 phase (reproductive phase) but many cells are cycling through the G0 phase (on vacation or unemployed) at any one moment, so we need to repeat chemotherapy in order to catch all neoplastic cells in their G1 phase.
Fundamental Hallmarks of Cancer (9)
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Evading apoptosis
- Limitless reproductive potential
- Sustained angiogenesis
- Tissue invasion and metastasis
- Deregulated metabolism
- Evading the immune system
- Unstable DNA
Hallmarks of Cancer:
New dimensions published in 2022 (4)
Phenotypic plasticity and disrupted
differentiation
Non-mutational epigenetic reprogramming
Polymorphic microbiomes
Senescent cells, of varying origins – in particular in the tumor microenvironment
Define apoptosis.
Controlled cell death without inflammation.
Smart reuse of cell components. Malfunctioning cells have to exit cell cycle.
Fundamental Hallmarks, Evading apoptosis:
In cancer; cells escape apoptosis. Malfunctioning cells remain cycling and more defects are allowed to be incorporated.
The tumor suppressors are gate keepers in the cell cycle and force defective cells into apoptosis. In cancer, tumor suppressor genes are down regulated or mutated (think BRCA gene etc.).
PGE2 has been proven to help cells to resist
apoptosis.
COX-2 inhibitors can promote cancer cells to undergo apoptosis (e.g. firocoxib etc.).
Fundamental Hallmarks, Sustained angiogenesis in cancer:
Already at a very small size, diffusion is not enough for cancer cells to survive. Hypoxia occurs and stimulates angiogenetic signals.
Tumor cells express many of the important proteins involved in this process. Tumors often overexpress VEGF (vascular endothelial growth factor).
PGE2 stimulates angiogenesis in normal tissue and tumors.
Tumors have incompetent and rapid angiogenesis leading to formation of leaky vessels. This promotes metastasis.
COX-2 inhibitors can slow down cancer cell
angiogenesis.
Fundamental Hallmarks, Tissue invasion and metastasis:
Metastasis is a pathogenic agent’s spread (e.g. tumor cell) from an initial or primary site to a different or secondary site within the host’s body.
Required for metastasis: tissue migration, penetration of vessel, escaping immune system in circulation, homing and
penetration vessel again, tissue migration and recolonization.
Heterogeneity leads to higher possibility for
metastasis.
Matrix metalloproteinases (MMPs) are capable of degrading all kinds of extracellular matrix proteins and enhance metastasis.
PGE2 promotes the function of MMPs.
COX-2 inhibitors can reduce metastatic potential.
What type of cancer is more prone to metastasis?
Mets are characteristic for low differentiated cancers with more pluripotent phenotype, meaning:
cells with lower differentiation features (anaplastic) (e.g. liver cancer cells in the liver that don’t really look much like liver cells) metastasize much easier (worse prognosis). If they look more like their host tissue, they tend to stay put better.
Pluripotent cells have increased treatment
resistance.
The cancer stem cell (CSC) theory has emerged as an attractive hypothesis for tumor development and progression.
One small subset of cancer cells has the
characteristics of stem cells.
CSCs have the capability of both self-renewal and differentiation into diverse cancer cells, which play a decisive role in maintaining capacity for malignant proliferation, invasion, metastasis,
and tumor recurrence.
CSCs are involved in tumor metastasis, however, the details, and the possible relationship of CSCs, angiogenesis, lymphangiogenesis, and tumor metastasis needs more research.
Fundamental Hallmarks, Evading the immune system:
An suppressed immune system is Recognized as one of the most recent hallmarks of cancer.
Supported by reports of increased cancer
incidence in immune suppressed individuals (auto immune disease, AIDS and patient treated with immune suppressants).
+ Discovery immune suppressive T-cells (T-Regs) in tumors.
Also discovered: tumor-associated macrophages secreting immune suppressive cytokines.
Tumors strive to change the inflammatory
surrounding towards a chronic inflammatory state.
How to treat the immune system in order to reverse neoplastic evasion?
By Converting immune signaling (reduce presence of T-reg cells) in tumors, it leads to tumor responses meaning the body recognizes the neoplasm and begins to attack it.
Rodent models with immune activation leads to tumor prevention.
New immune oncology treatments are under development.
PD-1 blockers, IL-2 treatment and COX-2
inhibitors.
Cancer vaccines prevent tumor formation (HPV).
Autolytic cancer vaccines expose tumor neoantigens that lead to tumor specific immune response.
TME in oncology stands for
The tumor microenvironment (TME) contains many supporting cells that protect the tumor and help it to grow.
In the TME cells like M2, Tumor-Associated Macrophages and cancer associated fibroblasts are essential and have been correlated with worse outcome when high in numbers.
The tumor is more and more considered like an organ of its own.
Many new treatments are designed to strike against the TME, when the tumor cells themselves become treatment resistant.
The Tumor and chronic inflammation.
Inflammation stimulates MMPs (Matrix metalloproteinases) and VEGF (vascular endothelial growth factor) which both promote neoplastic activity.
Inflammatory players TNF, IL-1 and IL-6 also contribute to neoplasia.
Conventional cancer therapy vs
cancer stem cell targeted therapy vs
perivascular niche-targeted therapy?
Conventional cancer therapy will probably increase the number of drug resistant cells.
Cancer stem cell-targeted therapy may increase the probability to create
toxicity due to pan-target effects.
Perivascular niche-targeted therapy IF finding specific targets in the pre-metastatic niche this is the way forward!
