Table 1 Origin of metastatic colorectal carcinoma cells

Seed factors

Epithelial-to-mesenchymal transition (EMT)

• EMT postulates that tumor cells with mesenchymal characteristics develop from either epithelial stem cells or differentiated epithelial cells as a result of a gradual accumulation of gene mutations

Reentering mesenchymal-epithelial transition (MET)

• In contrast to EMT, MET involves extravasation, invasion, and proliferation at distant sites, followed by the re-expression of epithelial features

• EMT is thought to be reversible after the MET

• It is unclear how a group of seemingly random somatic mutations could plan the complex set of behaviors associated with the EMT, only for these behaviors to be largely reversed during the MET

Stem cell origin of metastatic tumor cells

• Populations of tissue stem cells may give rise to metastatic cancer cells

• The majority of tissues have cells that are semi-differentiated and capable of replacing dead or damaged cells as a result of normal wear and tear

• These undifferentiated or semi-differentiated cells, also known as tissue stem cells, are the source of metastatic malignancies

Autophagy and metastasis

• Autophagy allows cells to degrade cytoplasmic components in the lysosome, although autophagy has long been hypothesized to play a role in cancer metastasis

Metastatic dormancy

• Many patients experience a relapse with metastatic cancer months or years after primary tumor treatment due to a clinical phenomenon known as residual tumor cells that can go dormant and grow resistant to treatments

• Disseminated tumor cells maintain quiescence, a stable, non-proliferative cellular state, during the period between dissemination and metastatic expansion known as tumor dormancy

Tumor-secreted extracellular vesicles

• Exosomes, microvesicles, and recently discovered “large oncosomes” are examples of secreted vesicles or extracellular vesicles

• Extracellular vesicles are essential in mediating the interaction between tumor cells and host cells, which creates pre-metastatic niche for development of secondary sites

Tumor-secreted cytokines and chemokines

• Cytokines and chemokines produced by cancer cells have the ability to draw and activate particular cell types

• These substances have a variety of purposes, making them important mediators of interactions between cancer cells and their environment

Soil factors

The primary soil factors

• It is well established that the initial tumor microenvironment is essential for controlling cancer spread

• The seed-to-soil signaling events that explain how the seed changes the microenvironment have received increased attention in numerous research

Tumor-associated microphages (TAMs)

• Interleukin-4 (IL-4)-releasing CD4+ T cells trigger the alternatively activated cells known as TAMs

Mesenchymal stem cells (MSCs)

• It has been demonstrated that mesenchymal stem cells concentrate in breast carcinomas and integrate into the stroma surrounding the tumor

• It has been established that MSCs in the tumor stroma increase cancer cells’ capacity for metastasis, which depends on CCL5 signaling through its chemokine receptor CCR5

Endothelial cells

• Haplo deficiency of PHD2 normalized endothelium lining and vessel maturation, which enhanced tumor perfusion and oxygenation and restricted the capacity of cancer cells to migrate

• PHD proteins function as oxygen sensors and may influence oxygen delivery

Hypoxia in primary soil

• Because tumor cells multiply quickly, the tumor frequently outgrows its blood supply, which causes significant hypoxia

• Long-standing research has shown that hypoxia encourages aggressive tumor characteristics, as well as tumor invasion and metastasis

• Hypoxia activates Jagged2 in breast cancer cells, initiates EMT, and improves cell survival in vitro, according to research into the molecular mechanism of Notch-ligand activation by hypoxia in primary soil

The secondary soil factors

• It is possible that “secondary soil” elements, such as the microenvironment of a distant organ or the milieu of a metastatic lesion, play a crucial role in fostering colonization and metastasis expansion

• The secondary soil is made up of a variety of elements and cell types that affect the spread of cancer. The pre-metastatic niche has been mostly induced by the intrinsic programs of tumor cells, according to research to date