Tumor Biology: (13) Invasion and metastasis of tumors

1 Preface

In the early stages of tumor multi-stage evolution, tumor cells proliferate indefinitely in the primary lesion, and it often takes several years to form an obvious primary tumor lesion

Although primary tumors are very dangerous, they only cause death in about 10% of tumor patients, and about 90% of tumor patients eventually die from the growth

The spread of tumor cells is the most dangerous process

Aggressiveness in tumor development depends primarily on complex biochemical and biological changes in the tumor cells themselves and associated matrices

2 Invasion-transfer cascade

Malignant tumors of epithelial origin and other tissues, such as tumors of connective and neural tissues, have similar patterns of

The entire process of the invasion-transfer cascade is profiled into 7 independent steps

Eventually, some tiny metastases acquire the ability to "clonalize" at the site of attachment, forming metastases

Recent molecular and cell biology studies, describing this process with another two-stage invasion-metastasis cascade theory: the first stage is the physical spread of tumor cells from the primary tumor to distant tissues and organs; The second stage of "cloning" relies on the adaptation of disseminated tumor cells to the distant tissue microenvironment

3 Clone formation

Once metastatic cancer cells reach the parenchymal tissue, they can proliferate to form small clusters of disseminated cancer cells called tiny metastases

The probability of a single cancer cell successfully completing all the steps of the invasion-metastasis cascade is very low

4 Phenotypic changes that invade cancer cells

In order to gain the ability to move and attack, cancer cells must lose the phenotype of many epithelial cells, change the metamorphosis, detach from the epithelial layer, and undergo a series of significant changes in a process called epithelial mesoelectroelial transformation (EMT

The PHENOMENON PHENOMENON CAN BE SEEN AT THE EDGE OF TUMORS THAT INVADE ADJACENTS, A PATHOLOGICAL PROCESS VERY SIMILAR

In normal and pathological state of EMT, in addition to involving changes in cell morphology and acquisition of motility, the cellular gene expression profile has also changed

5 Role of stromal cells

Convincing experimental data suggest that the aggressive metastasis ability of mouse breast cancer cells, in this case, mainly macrophages, is significantly influenced by stromal cell

In vivo and in vitro experimental results of mouse breast cancer cells show that EGF is the main inducer of cancer cell invasion

Macrophages play a key role

These data suggest that cancer cells acquire malignant phenotypes, including EMT, and are not just determined by the genomes of
these cells.
In fact, cell phenotype transitions are usually determined by a combination of signals from alleles of specific mutations in the cancer cell genome and the microenvironment of surrounding tissues, particularly the interstitial synergy at the junction of tumor epithelium and reactive matrix
.
In a variety of tumors, the transmission of this interaction signal is mediated
by specific factors secreted by the reactive matrix such as TGF-β, Wnt, PGE2, and TNF-α.

6 The key role of extracellular proteases

EMT represents the replication biological process by which cancer cells acquire the ability to invade and motility, which includes a number of important effector molecules, the most important of which is matrix metalloproteinase (MMP
).
The interstitial cells recruited in tumors are mainly macrophages, mast cells, and fibroblasts, which are able to secrete large amounts of proteases
.
By dissolving the thick matrix molecules in the tissue that surround the cell, MMP creates space
for the movement of the cell.

MMP degraded ECM components include fibrinogen, mucin, laminin, collagen and proteoglycans
.
In the process of degrading ECM components, MMP can also mobilize and activate specific growth factors that would otherwise be inactive form wrapped around the ECM or around
cells.

A key molecule that complements the function of these secretory MMP is MT1-MMP, which is directly anchored to the surface of the plasma membrane of cancer cells, cutting and degrading extracellular matrix components, cells indicating adhesion to molecules, and growth factor receptors and chemokines
.
It can also lyse inactivated enzymatic progens into enzyme-active MMP molecules
.

MT1-MMP activity plays a leading role in the disintegration of the basement membrane, and in the early stages of malignant progression, the MT1-MMP shown by cancer cells can cleave type IV collagen that confers a rigid role on the basement membrane, and the loosening of the basement membrane causes cancer cells to begin to invade the underlying matrix
.
Once in the matrix, the invading cancer cells are blocked by a network of cross-linked type I collagen fibers, at which point MT1-MMP once again plays a key role
.
MT1-MMP degrades type I collagen and cleaves inactive proenzymes (MMP-2 precursors)
derived from activated matrix.
Activated MMP-2 further cleaves type I collagen into low molecular weight fragments
in the space around the cell.

7 Transfer inhibitory genes

The invasion-transfer cascade involves many genes whose protein products serve as components
of many complex regulatory loops that control cell physiology.
Like all finely regulated loops, they contain both positive and negative regulators to ensure the correct output of the finely regulated
signal.
These negative regulators, similar to tumor suppressors, are called metastatic suppression genes, which specifically inhibit metastasis without affecting primary tumor growth
.
For example, p53's close relative p63, p53 inhibits p63 function by forming a heterologous tetramer with p63, thereby increasing the tendency to metastasis
.

The inhibitory function of P63 comes from its ability to promote Dimer expression, a gene product that is an enzyme in the final step of microRNA processing, and its expression level is down-regulated in relation to
increased tumor aggressiveness.
Other transfer inhibition genes, including proteins encoded by E-cadherin, RhoGDI-2, and TIMPs, are important players in known biological mechanisms
of invasion and transfer.

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