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(2) INSENSITIVITY TO ANTI-GROWTH SIGNALS

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(2) INSENSITIVITY TO ANTI-GROWTH SIGNALS

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(A) Introduction:
1. Cells receive growth (+) or anti-growth (-) signals externally.
2. There are two types of anti-growth signals: soluble growth inhibitors and immobilized growth inhibitors (embedded in the extracellular matrix and on surfaces or nearby cells).
3. These signals are received by transmembrane receptors and then transduced from cell surface receptors into cells via proteins and cascades.
4. Depending on the external environment, cells decide whether to proliferate, to be quiescent, or to enter into a postmitotic state.

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Acquired Capability: Evading Apoptosis

Ability of tumor cells determined by the rate of proliferation and rate of attrition.

Programmed cell death – apoptosis – represents the major role of attrition.

Apoptosis (Figure)– Disruption of cellular membrane, broken down of the cytoplasmic and nuclear skeletons, extrusion of the cytosol, degradation of the chromosomes, and the fragmental of the nucleus. In the end, the apoptotic bodies (cell corpse) is engulfed by nearby cells.

Apoptotic machinery – sensor (ligand) and effector (signal).

sensor – Monitor the intracellular and extracellular environment which influence the determination of the cell whether the cell should live or die. Include cell surface receptor that bind to survival or death receptor.

effector – Regulates by the sensor components. Involve the members of Bcl-2 proteins family, either proapoptotic or antiapoptotic protein function.

| > proapoptotic | > apoptosis |
| > antiapoptotic | < apoptosis |
'>' high
'<' low

Reduce in rate of apoptosis resulting in survival of tumor and cancer cells.

“Apoptosis serves as a barrier to cancer”

Increase of cells population will induce the pathway of cell death, resulting to increase of apoptosis.

Shows important role of apoptosis in tumor/cancer survival.

Upregulation of the antiapoptotic genes resulted to the reduction in cells apoptosis.

Co-expression of anti-apoptotic and oncogene – promote formation of tumor by enhancing cell survival, not by further inducing cell proliferation.

Increase in cell proliferation only resulted to the increase of apoptosis rate. Thus, this process must be accompanied by the deregulation of apoptotic or antiapoptotic protein that will be resulting to the decrease in cells apoptosis which lead to tumor survival.

Evidence of the capability to evade apoptosis

1. The inactivation of the pRB (tumour suppressor protein) shows a slow tumour growth and having a high apoptotic rate. With additional inactivation of the p53 (tumour suppressor protein), the tumour started to grow rapidly. This shows that p53 protein plays parts in the apoptotic signalling pathway and by inactivating it can weaken the apoptotic mechanism (Symonds et al. 1994).

2. Tested on mice, if IGF-2 was knockout, the tumour growth was impaired because there shows a high rate of apoptosis. This deduces that the absence of IGF-2 did not affect the cell proliferation rates but act as the antiapoptotic factors (Christofori et al. 1994).

3. Recently they found cancer cell presenting a FAS ligand defects which will not produce any downstream signalling for apoptosis (Pitti et al. 1998).

Conclusion

A lot of regulatory and effector components are present in a redundant form. Due to redundancy, it affects the production of antitumor therapy. Hoping that the new emerging technologies can display the apoptotic pathways still operative in specific types of cancer cells and new 🤬 capability to cross-talk between components of parallel apoptotic signalling pathways in tumour cells could restore the apoptotic defence mechanism.

Reference

Symonds, H., Krall, L., Remington, L., Saenz-Robles, M., Lowe, S., Jacks, T., & Van Dyke, T. (1994). p53-Dependent apoptosis suppresses tumor growth and progression in vivo. Cell, 78(4), 703–711. doi:10.1016/0092-8674(94)90534-7

Christofori, G., Naik, P., & Hanahan, D. (1994). A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature, 369(6479), 414–418. doi:10.1038/369414a0

Pitti, R. M., Marsters, S. A., Lawrence, D. A., Roy, M., Kischkel, F. C., Dowd, P., … Ashkenazi, A. (1998). Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature, 396(6712), 699–703. doi:10.1038/25387

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From 2000 papers
Introduction

Normal cells need mitogenic growth signals to proceed from the quiescent (dormant) phase to the proliferative phase.

Signals are transmitted into the cell by transmembrane receptors.

Classes of signaling molecules:

Diffusible growth factors,

Extracellular matrix components, and,

Cell-to-cell adhesion/interaction molecules.

Many oncogenes mimic normal growth signaling.

Display greatly reduced dependence on exogenous growth stimulation from the normal tissue microenvironment.

Disrupts homeostasis.

Three common molecular strategies for achieving self sufficiency in growth signals:

1. Alteration to Extracellular Signals:
While most soluble mitogenic growth factors (GFs) are made by one cell type in order to stimulate proliferation of another—the process of heterotypic signaling—many cancer cells acquire the ability to synthesize GFs to which they are responsive, creating a positive feedback signaling loop often termed autocrine stimulation . Clearly, the manufacture of a GF by a cancer cell obviates dependence on GFs from other cells within the tissue. The production of PDGF (platelet-derived growth factor) and TGFα (tumor growth factor α) by glioblastomas and sarcomas, respectively, are two illustrative examples .

2. Alteration to Transcellular ransducers of Signals :

Cell surface receptors become targets of deregulation during tumor pathogenesis.

Deregulation of Cell Surface Recellsceptors by Overexpression

Growth factor receptors carrying tyrosine kinase activities in their cytoplasmic domain are often overexpressed in many cancers.

Enable cancer cell to become hyperresponsive to ambient (normal) levels of growth factors, that normally would not elicit a response.

E.g. Overexpression of EGF-R/erbB in stomach, brain and breast tumors; HER2/neu receptor overexpressed in stomach and mammary carcinomas.

Ligand-Independent Signalling

Overexpression (causing close proximity between receptors) or structural alterations (e.g. permanent dimerization of receptors) to receptors can elicit ligand-independent signaling as shown below

Switching of ECM Receptors (Integrins) Expressed to Favour  Progrowth Signals

Receptors physically link cells to extracellular superstructures known as the extracellular matrix (ECM).

Successful binding to integrins favoring progrowth signals → influence cell behavior (e.g. transition from quiescence to motile phase, resistance to apoptosis, and entrance into active cell cycle.)

Failure to bind to integrins favoring progrowth signals → impairs cell motility, induce apoptosis and cause cell cycle arrest.

These three ways to alter transcellular receptors can activate the SOS-Ras-Raf-MAP kinase pathway, a signaling pathway involved in the regulation of genes associated with processes such as apoptosis and differentiation (BioVision Incorporated, n.d.)

3. Alteration to Intracellular Circuit :

Alteration of Cytoplasmic Circuitry: One of the most complicated mechanisms of acquired GS autonomy. In this mechanism, GS autonomy derive from alterations in components of the downstream cytoplasmic circuitry that receives and processes the signals emitted by ligand-activated GF receptors and integrins and  SOS-Ras-Raf-MAPK cascade plays a central role here.

Altered forms of Ras Protein: Ras proteins are a closely related family of proteins that transmit signals for cell division in humans. Growth signals are received from outside the cell by receptors at the cell surface. The activated receptor transfers the signal to intracellular Ras protein. Ras is a G-protein, and after receiving a signal, normal Ras protein binds guanosine triphosphate (GTP) and enters signal-emitting mode. After transmitting a brief pulse of signals, Ras splits the GTP into guanosine diphosphate (GDP) plus phosphate and relapses into standby mode again. The cancer-causing form of the Ras protein is locked permanently into the signal-emitting mode and never splits the GTP. Therefore, it constantly floods the cell with signals urging cell division, even when none is received from outside. The ras oncogene is the result of a single base change in the structural region of the gene. This causes an alteration in a single amino acid in the encoded protein .Most ras mutations alter the amino acid at position 12; others affect position 13 or 61.Only a few very specific mutations can create a ras oncogene from the proto-oncogene.The consequence of hyperactivation of Ras is uncontrolled cell division and the beginnings of a possible cancer. Mutations of ras are found in about 25% of cancers and have been analyzed in detail in cancers of the lung, colon, pancreas, and thyroid.

Conclusion

Contributions of the Ancillary Cells

E.g. fibroblasts, endothelial cells

Normal tissues: Cells instructed to grow by their neighbors via paracrine or endocrine signaling.

Growth signals driving the proliferation of carcinoma cells may originate from the stromal cell components of the tumor masses.

From 2011 paper
Somatic Mutations Activate Additional Downstream Pathways

Somatic mutations in certain human tumours : predict constitutive activation of signalling circuits triggered by activated GFRs.

Example:

Mutations affecting structure of B-Raf protein, resulting in constitutive signalling through Raf to MAP-kinase pathway.

Disruptions of Negative-Feedback Mechanisms that Attenuate Proliferative Signaling

Example 1: Oncogenic mutations affecting ras → compromise Ras GTPase activity

Normal: intrinsic negative-feedback mechanism (ensures active signal transmission is transitory.)

Example 2: Negative feedback mechanism causing mTOR activation → inhibition of PI3K

mTOR: coordinator of cell growth and metabolism

PI3K: generates phosphatidylinositol-3,4,5-trisphosphate for translocation of AKT to plasma membrane

Cells achieve proliferative independence → development of adaptive resistance toward 🤬 targeting mitogenic signalling.

Excessive Proliferative Signaling Can Trigger Cell Senescence

Excessively elevated signaling by oncoproteins (e.g. RAS, MYC, RAF) → counteracting responses from cells (e.g. induction of cell senescence and/or apoptosis)

Cells expressing lower levels of oncoprotein may avoid senescence and proliferate.

Oncogenic signaling depends on compromises between maximal mitogenic stimulation & avoidance of antiproliferative defenses.

(Some) adapt to high levels of oncogenic signaling by disabling senescence or apoptosis circuitry.

Enabling Characteristics
1. Genome Instability and Mutation

Certain mutant genotypes confer selective advantage on cells → outgrowth, eventual dominance in local tissue environment.

Tumor progression triggered by chance acquisition of enabling mutant genotype.

Increased rate of mutation in cancer cells during progression.

Through increased sensitivity to mutagenic agents, breakdown in genomic maintenance machinery, or both.

Defects in detecting DNA damage & activating repair machinery

Defects in direct repair of damaged DNA

Defects in inactivating or intercepting mutagenic molecules before DNA damage

Function loss through inactivating mutations or via epigenetic repression.

Also, the loss of telomeric DNA in tumours → karyotypic instability, amplification & deletion of chromosomal segments.

Recurrence of specific aberrations (amplifications & deletions) at particular sites in the genome

These sites likely to harbor genes, when altered, favor neoplastic progression,

2. Tumor-Promoting Inflammation

Tumours densely infiltrated by immune cells

Mirror inflammatory conditions in non-neoplastic tissues

Probably as an attempt by the immune system to eradicate tumours

Inflammation → bioactive molecules and inductive signals

Bioactive molecules → sustain proliferative signaling, limit cel death, invasion, metastasis.

Inductive signals → activation of EMT

Additionally, inflammatory cells → chemicals (e.g. ROS)

Actively mutagenic for cancer cells

Accelerates genetic evolution towards heightened malignancy.

Additional Sources:

MAP Kinase Pathway. (0AD). Retrieved from https://www.biovision.com/products/signaling-pathways/map-kinase-pathway.html

Ras protein pathway. Retrieved from

https://www.sciencedirect.com/topics/neuroscience/ras-protein

Growth facrors

Holland-Frei Cancer Medicine, 6th edition

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[Intro]
Angiogenesis is defined by the formation of new blood vessels from existing blood vessels.

[What affects angiogenesis?]
The counterbalancing of positive and negative signals will either block or induce angiogenesis.

Initiating signals: vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (FGF 1/2)

Inhibiting signals: thrombospondin-1

[When?]
In human cancers, we can expect angiogenesis to be an early to mid stage event.

[How to turn on 'angiogenic switch'?]
The 'angiogenic switch' can be controlled by counterbalancing the angiogenesis inducers and countervailing inhibitors.

A common strategy deployed by tumours often involves altered gene expression. Tumours are shown to have increased levels of VEGF and/or FGFs compared to normal tissue. In others, expression of inhibitors is down regulated.

[What are the exact mechanism(s) of turning on “angiogenic switch”?]
At the time of the research, there was no exact mechanism for turning on the angiogenic switch was not completely understood.

The inhibitor, thrombospondin-1, has been shown to be upregulated by the p53 tumour suppressor protein in certain cell types. Consequently, the loss of p53 can cause to drops in thrombospondin-1 levels.

Additionally, the VEGF gene is also under complex transcriptional control. Activation of the ras oncogene or loss of the VHL tumour suppressor gene in certain cell types leads to the upregulation of VEGF expression.

[Other ways?]
Proteases! A variety of proteases can release bFGF stored in the ECM. Plasmin (a type of protease) a proangiogenic component of the clotting system can cleave itself into an angiogenesis inhibitor form called angiostatin.

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LIMITLESS REPLICATIVE POTENTIAL

Cells carry an intrinsic, cell-autonomous programs that limits multiplication. This program operate independently of the cell to cell signalling pathway.

In order for tumour cell have limitless replicative potential, the cells need to:-

1)    OVERCOME SENESCENCE

Cells in culture have a finite replicative potential. After a certain number of doubling, they undergo senescence.

A.    Disabling pRb and p53

·      Senescence can be avoided by disabling pRb and p53, but they enter crisis.

·      Crisis state is characterized by massive cell death, karyotypic disarray associated with end-to-end fusion of chromosomes and occasional emergence of a variant that has the ability to multiply without limit; immortalization.

·      Perhaps only 1 in 107 cells get immortalized.

·      Formation of tumors is, in most cases, dependent on the evolution of cells that escape from the barriers that senescence and crisis present to unlimited proliferation. Cells that achieve this are referred to as “immortalized”.

2)    OVERCOME TELOMERE SHORTENING (TELOMERE MAINTAINANCE)

Telomeres are repetitive sequences at the end of the chromosome that protects the end from end-to-end fusion with other chromosomes and deterioration. In normal cells, after  each cell division some of the telomere is lost; telomere shortening. When the telomere becomes too short, the chromosomes reaches a “critical length” and no longer replicate. The cell then dies via apoptosis.

Most cancer cells succeed in telomere maintenance by upregulation of telomerase and the remaining cancer cells activates a mechanism called ALT, Alternative lengthening of telomeres.

A.    Upregulating telomerase

·      Telomerase is a telomere-elongating enzyme that adds hexanucleotide repeats onto the ends of telomeric DNA.

·      Telomerase are normally found in fetal cells, germ cells and tumour cells. They are not found in normal adult somatic cells.

·      Upregulation of telomerase allows the tumour cells to maintain the telomere at a length above a critical threshold, that allows unlimited multiplication of descendant cells.

·      Mice carrying mutation in p16INK4A (cell cycle inhibitor) and lacked telomerase show reduced tumor incidence.

·      Meanwhile, mice carrying mutation in p16INK4A that are tumor prone, shows elevated telomerase activity.

B.    ALT. Alternative lengthening of telomeres

·      ALT is a telomerase independent mechanism of telomere maintenance by recombination-based interchromosomal exchange of sequences or homologous recombination (HR).

·       ALT is activated in tumors of mesenchymal or neuroepithelial origin.

·      The exact mechanism behind telomere maintenance in the ALT pathway is unclear, but likely involves multiple homologous recombination events at the telomere.

·       ALT is proposed to utilize telomeric templates for synthesis; however, its precise protein requirements have remained elusive.

·      A proposed model for ALT is where telomeric 3′ overhangs become extended by invading other telomeric DNA and using it as a template for DNA replication. The other telomeric DNA can be: part of the same telomere (through telomere-loop formation); in a sister chromatid; in the telomere of another chromosome; or in one of the forms of extrachromosomal telomeric DNA.

·       It is currently not clear whether there is more than one ALT mechanism in mammalian cells and there is no assay for ALT activity.

NOTES:

Senescence: Growth arrest, continued metabolic activity without widespread cell death

pRb and p53: Tumor suppressor genes

References

Cesare AJ, Reddel RR. Alternative Lengthening of Telomeres in Mammalian Cells. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6486/

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From the 2000 paper:

Some primary tumor cells acquire the ability to undergo invasion and metastasis whereby they leave their original location and move into the surrounding tissue. They eventually travel to distant sites in the body, forming new colonies and secondary tumors. It is almost always these metastases, rather than the primary tumor, which causes ultimate death. The new metastatic colonies resemble cells from their site of origin and disrupt the functioning of the host organ. Metastatic breast cancer in the lungs is still breast cancer, not lung cancer.

The ability to metastasize allows cancer cells to find new areas of the body where space and nutrients are not limiting. How do cancer cells do this?

THE EXTRACELLULAR MATRIX

Our tissues are not made up solely of cells. A large proportion of tissue consists of extracellular space, which is filled with a mixture of carbohydrate and protein molecules and this space is known as the Extracellular Matrix (ECM). The molecules that make up the ECM are secreted by cells embedded in it, and these cells tether themselves to the ECM (and to one another) to form tissues. Metastasis therefore requires the untethering of these bonds, to allow cancer cells to migrate freely.

Several classes of proteins are involved in the tethering of cells to their surroundings. Immunoglobulins and cadherins mediate cell-to-cell adhesions while integrins link cells to the ECM. All of these interactions convey regulatory signals to the cell and should not be viewed as static connections that simply hold cells in place.

(A) E-cadherin

The most important protein cementing cells to each other is known as E-cadherin. The coupling of cells by E-cadherin results in the transmission of antigrowth signals; this is one of the mechanisms for the phenomenon known as contact inhibition, where cells that touch one another do not grow any further. Unsurprisingly, E-cadherin function (to suppress) is lost in migrating cancer cells.

(B) N-CAMs

Normal form of adhesive N-CAMs is crucial in suppressing metastasis. Hence, switching of expression in N-CAM from a highly adhesive isoform to a poorly adhesive (or even repulsive) isoform in Wilms tumor, neuroblastoma, and small cell lung cancer, and reduction in overall expression level in invasive pancreatic and colorectal cancers may lead to metastasis.

C) Integrins

Invasiveness and metastases are brought upon by changes in the expression of integrins. Integrins are transmembrane cell adhesion proteins that act as matrix receptors and tie the matrix to the cell cytoskeleton. Integrins are heterodimeric receptors with alpha and beta subunits. More than 22 different subtypes of alpha and beta subunits exist, for example, alpha-beta1 and alphaV-beta3, each with distinct substrate preferences. Shift in the expression of integrin subtype resulting in preferential binding with degraded stromal components over ECM promotes invasion and metastasis.

D) Extracellular Proteases

Matrix degrading proteases are characteristic to cell surface membranes of cancer cells. They facilitate invasion into nearby stroma, across blood vessels and through normal epithelial cell layers. In cancer cells, these protease genes are upregulated, protease inhibitor genes are down regulated and inactive zymogen forms of proteases are converted into active enzymes. On many occasions, stromal and inflammatory cells are induced to produce proteases that would eventually be picked up by receptors on carcinoma cells. Therefore, cancer cells with proteases on their surfaces can degrade ECM through proteolytic interaction in order to metastasize.

What are the traits of migrating cancer cells? These cells change their appearance, from a neat, ordered cobblestone-like shape to spindly and long-limbed. The cells also untether themselves from the ECM, by expressing proteins that degrade the ECM. They stop expressing E-cadherins so that the cement that binds them to other cells is eliminated. They express more N-cadherins, so they can move through blood vessels to distant sites more efficiently.

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From the 2011 paper:

Malignancy in carcinoma cells from epithelial tissues is seen as they upgrade pathologically, promote local invasion, distant metastasis and alter their shape and attachments with other cells and the extra-cellular matrix. One of the major characterisation of cancer is the loss of E-cadherins. E-cadherins are cell-to-cell adhesion molecules (CAMs) which are important for the formation and maintenance of adherent junctions in areas of epithelial cell-cell contact. Downregulation and mutational inactivation has been shown to be linked to promotion of invasion and metastasis of cancer cells and vice versa. Another cell adhesion molecule that has its expression altered in aggressive carcinomas is N-cadherin. These molecules are found in migrating neural cells and mesenchymal cells thus playing an important role in migrations and in inhibition of cytostasis. Genes for these molecules are upregulated in invasive carcinomas.

The invasion and metastasis cascade is multi-factorial and a multi-step process. Further researches have been carried on to find contributory factors to this phenomenon, some of which will be discussed below.

Invasion-metastasis cascade:

1)    Cellular changes

2)    Local invasion

3)    Intravasation of cancer cells into blood and lymphatic vessels

4)    Movement through lymphatic and hematogenous system

5)    Extravasation into parenchyma of distant cells.

6)    Formation of small modules of cancer cells

7)    Colonisation: growth spurt of microcolonies of cancer cells.

EMT program broadly regulates I&M
Known as the epithelial-mesenchymal transition, EMT is a developmental regulatory program where epithelial cells lose cell polarity and cell-cell adhesion to transform into mesenchymal cells with resistance to apoptosis, migratory and invasive properties. Carcinoma cells acquire EMT in similar processes that are involved in embryonic morphogenesis and wound healing. This process is regulated by a set of pleiotropipc transcriptional factors such as Snail, Slug, Twist and Zeb1/2. These factors are overexpressed in different combinations in various cancer models to elicit invasion and metastasis. They bring about loss of adheren junctions, conversion from a polygonal/epithelial to a spindly/fibroblastic morphology, expression of matrix-degrading enzymes, increased moltility, increased resistance to apoptosis and direct repression of E-cadherin gene expression, thus, removing key suppressors to motility and invasiveness. Cancer cells in interaction with tumour stromal cells in their microenvironment induce EMT transition, regulated by these genes.

Heterotypic contributions of stromal cells

Interaction between cancer cells and the cancer related stromal cells provoke invasion and metastasis in a feedback loop system. Example: Mesenchymal stem cells (MSCs) in the tumour stroma secrete CCL5/RANTES in response to cancer cell signals which in turn stimulates invasive behaviour in cancer cells. Furthermore, macrophages supply tumour degrading enzymes such as metalloproteinases and cysteine cathepsin proteases to facilitate local invasion. They are activated by the IL-4 produced by cancer cells. In an example of metastatic breast cancer, tumour associated macrophages (TAMs) supply epidermal growth factor, EGF, to breast cancer cells which in turn stimulates macrophages with CSF-1.

These interactions show that malignant tumours are subjected to multiple contributory factors.

Plasticity in the invasive growth program

Signals inducing invasion (may be through EMT) means there is a possibility of reversibility. For example, when secondary cancers may no longer benefit from activated stroma and EMT-inducing signals AND/OR when there is absence of these signals, then these cancer cells may change to become invasive. This is called mesenchymal-epithelial transition or MET. This plasticity (the adaptability of an organism to changes) may lead to formation of NEW tumour colonies OR tumours of similar pathology of its primary cancerous state.

Distinct forms of invasion --> different cancer types

Other than the abovementioned MET invasion type, there are two other types that were discussed in this paper, which are namely collective invasion and ‘amoeboid’ form of invasion. Collective invasion happens when nodules of cancer cells advance to adjacent tissues but do not metastasise (e.g. squamous cell carcinomas rarely metastasise which means these cells lack the metastasis ability). The latter one, the ‘amoeboid’ form occurs when individual cancer cells show morphological plasticity where these cells can slither through existing interstices in ECM rather than clearing a path like the previous two types of invasion. However, it is not clear whether collective invasion and ‘amoeboid’ form of invasion are EMT-related.

Another emerging concept is invasion by inflammatory cells that cluster at boundaries of tumours producing ECM-degrading enzymes thus promoting invasion. It may or may not be via EMT that these enzymes secrete chemoattractant to recruit such pro-invasive inflammatory cells.

Complexity of metastatic colonisation

Firstly, metastasis is defined by physical movement of primary tumour cells to travel to distant places and the adaption of these cells to foreign microenvironments. However, the ability of cancer cells to metastasise is much more complex than we thought.

(1) Microstases

Colonisation is not necessarily coupled with dissemination. Primary tumour cells may release systemic suppressor factors that can somehow render these microstases dormant where they do not become macrostases. Afterwards, when these cells are resected, they quickly explode (become macrostases) but in breast and melanoma cancers, this exploding process happens after decades (i.e. after surgery).  Other than that, some microstases may lack other hallmarks of cancer, or they may suffer from nutrient starvation that forces them to go through autophagy (shrinkage leads to reverting to invasive state). There are other mechanisms proposed such as a) the antigrowth signals in ECM and b) the immune system suppressing these microstases to stay inactive.

(2) Adaptation

There is a notion that states that the most disseminated cancer cells are the most poorly adapted (at least, initially) as these cancer cells need to have ad hoc solutions using different programs to be able to thrive in the new environments. In the previous paper, it is thought that metastasis is the final step (among all 6 hallmarks) for these cells to be considered cancerous but they found that there is early dissemination of such cells (where they have not acquired the former 5 hallmarks). This means that metastasis could happen at different timings and even be tissue-specific. Lastly, some cancer cells, however, need not go through much changes if the microenvironments are preordained/permissive to these cells.