Tumor spread, also known as metastasis, occurs when cancer cells break away from the original tumor and travel through the body via the blood or lymph system to form new tumors in other organs or tissues. This process allows cancer to advance, worsen prognosis, and become more difficult to treat. Understanding the biology behind metastasis is key to developing new therapies that can prevent or slow the spread of cancer.
What is metastasis?
Metastasis is a complex, multi-step process that enables cancer cells to spread from their original site to distant organs or tissues in the body. The key steps involved include:
- Local invasion – Cancer cells first invade nearby normal tissue.
- Intravasation – Cancer cells enter the circulation by passing through blood vessel walls or lymph vessel walls.
- Survival in circulation – Cancer cells must survive the harsh conditions of blood/lymph circulation, avoiding immune detection.
- Extravasation – Cancer cells arrest in small blood vessels/lymph vessels of distant tissues and exit into the surrounding tissue.
- Micrometastasis – Small clusters of cancer cells proliferate at distant sites to form micrometastases.
- Colonization (macrometastasis) – Micrometastases develop their own blood supply and grow into clinically detectable macrometastases or secondary tumors.
This complex process allows cancer cells to spread throughout the body, causing secondary tumors far from the original cancer site. Metastasis is responsible for around 90% of cancer deaths.
What factors influence metastasis?
Metastasis depends on multiple cellular traits that allow cancer cells to complete each step of the metastatic cascade. Key factors that influence metastatic ability include:
Genetic mutations
– Mutations in oncogenes (cancer-promoting genes) or tumor suppressor genes alter molecular pathways inside cancer cells, enabling properties like increased survival, invasion, and motility.
– Common examples include KRAS, BRAF, P53, and PTEN mutations.
Epithelial-mesenchymal transition (EMT)
– EMT enables cancer cells to lose intercellular adhesion properties and gain a more motile, invasive phenotype.
– Master regulator transcription factors like Snail, Slug, Twist, and Zeb drive EMT.
Ability to intravasate
– Cancer cells secrete proteins like matrix metalloproteinases (MMPs) to break down proteins in the extracellular matrix surrounding blood vessels. This facilitates entry into circulation.
Anoikis resistance
– Normal epithelial cells undergo programmed cell death (anoikis) when detached from their extracellular matrix. Cancer cells develop mechanisms to resist anoikis after leaving their tissue of origin.
Ability to extravasate
– Adhesion molecules like integrins on cancer cells can bind to endothelial cells lining blood vessels at distant sites, triggering extravasation.
– Cancer cells often get mechanically trapped in small capillaries, facilitating extravasation.
Factors in metastatic niche
– Metastatic sites produce growth factors, inflammatory signals, and extracellular matrix components that support colonization and growth of incoming cancer cells.
What types of tumors are most likely to metastasize?
Cancer type and stage strongly influence metastatic potential:
Carcinomas
Cancers of epithelial tissue (carcinomas) make up ~90% of cancers and are far more likely to metastasize than other cancer types like sarcomas, lymphomas, etc. Common metastatic carcinomas include:
– Breast cancer
– Prostate cancer
– Lung cancer
– Colorectal cancer
– Pancreatic cancer
– Melanoma
High grade tumors
Higher grade tumors have more abnormal cytology, faster growth, and poorer differentiation. High grade carcinomas have higher metastatic potential.
Late stage tumors
Larger, later stage tumors have a greater chance that some cancer cells will gain metastatic abilities through accumulating mutations. Stage IV cancers by definition have metastases.
What are the most common sites of metastasis?
Metastatic patterns differ somewhat based on cancer type, however tumors often metastasize to:
Lungs
The highly vascular lungs are a common site for metastases from many cancer types due to the large volume of blood flowing from the heart. Breast, prostate, bladder, colon, and other carcinomas often metastasize to the lungs.
Liver
The liver filters large amounts of blood from the digestive tract. Breast, lung, and gastrointestinal cancers often metastasize to the liver.
Bones
Breast, prostate, and lung cancer cells have affinity for bone marrow and frequently cause bone metastases. The bone marrow microenvironment promotes growth of disseminated tumor cells.
Brain
Lung, breast, skin (melanoma), colon, and kidney cancers can metastasize to the brain, although this location requires cancer cells to cross the blood-brain barrier. Even a single brain metastasis can be devastating.
Lymph nodes
Metastasis to local and regional lymph nodes, which filter lymph drainage from tumors, is common early in cancer progression for carcinomas. This often guides treatment and prognosis.
What enhances the ability of cancer cells to metastasize?
Beyond inherent traits of cancer cells, certain factors help facilitate the metastatic process:
Tumor angiogenesis
– Growing tumors secrete VEGF and other factors that stimulate ingrowth of new blood vessels (angiogenesis). This provides an escape route for cancer cells to enter circulation.
Leaky blood vessels
– Abnormal tumor blood vessels have increased permeability, which enhances intravasation and extravasation of cancer cells.
Evading the immune system
– Cancer cells reduce surface MHC-1 to avoid detection by natural killer cells in circulation. Other immunosuppressive mechanisms help metastasizing cells evade the immune system.
Clotting around CTCs
– Platelet clotting around circulating tumor cells (CTCs) helps shield them from shear stress and immune attack during hematogenous dissemination.
Premetastatic niches
– Primary tumors can stimulate future metastatic sites to generate a pro-metastatic microenvironment even prior to arrival of cancer cells.
How is metastasis detected?
Detecting metastasis guides cancer staging and treatment planning. Common methods include:
Imaging
– CT, PET, MRI, and bone scans can reveal metastases in lymph nodes, internal organs, bones, and other tissues. Contrast agents and tracers help enhance detection.
Biopsy
– Needle or surgical biopsy of suspicious lesions can confirm metastatic disease through pathological analysis. Immunohistochemistry helps identify tissue of origin.
Liquid biopsy
– Analyzing CTCs or cell-free tumor DNA in blood via sensitive methods like PCR can detect genetic signatures of cancers and micrometastases.
Clinical examination
– Palpating for enlarged lymph nodes or abnormalities in organs like the liver during physical exam can reveal possible metastases.
How do tumors metastasize to the brain?
Metastasis to the brain presents unique challenges for cancer cells:
Crossing the blood-brain barrier
– Cancer cells must penetrate the BBB, which tightly controls passage of cells and molecules into the brain. Breaching the BBB relies on:
– Secreting factors like vascular endothelial growth factor (VEGF) to loosen tight junctions between endothelial cells.
– Co-opting transport mechanisms like receptor-mediated transcytosis used by nutrients to cross the BBB.
Adhering in brain capillaries
– Cancer cells adhere to capillary walls via adhesion molecule interactions, then extravasate into the surrounding brain tissue.
Interacting with brain microenvironment
– Astrocytes, neurons, and specialized extracellular matrix like heparan sulfate proteoglycans promote colonization of disseminated cancer cells in the brain parenchyma.
Forming the metastasis
– Brain metastases disrupt normal neural signaling. Metastatic lesions exhibit distorted vasculature with permeable BBB that facilitates their further growth.
How does the metastatic niche form?
The metastatic niche concept explains how disseminated cancer cells hijack secondary organs to form supportive microenvironments for metastasis:
Early signaling events
– Primary tumors secrete exosomes, proteins, and miRNAs that travel to future metastatic sites and begin remodeling the local microenvironment.
Formation of the pre-metastatic niche
– Arriving factors recruit bone marrow-derived cells and prime endothelial cells, macrophages, fibroblasts, and ECM at future metastatic sites before cancer cells even arrive.
Establishing the metastatic niche
– Incoming cancer cells then coinstruct stromal cells to sustain proliferation, survival, and colonization signals that enable formation of macrometastases.
Sustaining metastasis
– Continued interplay between cancer cells and recruited fibroblasts, endothelial cells, pericytes, macrophages, and ECM maintains a self-reinforcing microenvironment that fuels metastatic outgrowth.
What therapeutic strategies target metastasis?
Current approaches to specifically target metastasis include:
Preventing early dissemination
– Adjuvant chemotherapy after primary tumor removal aims to eradicate micrometastases before they colonize.
Targeting metastatic mediators
– Drugs inhibiting MMPs, integrins, growth factors, and other metastatic drivers seek to disrupt parts of the cascade.
Blocking colonization
– Targeting coinstruction interactions and survival signaling in the metastatic niche could prevent colonization.
Immunotherapy
– Checkpoint inhibitors boost anti-tumor immune responses against metastases. Vaccines may also target metastatic disease.
Identifying high-risk patients
– Gene expression profiles, circulating tumor cell analysis, and other emerging biomarkers could identify patients needing intensive anti-metastasis therapy.
Conclusion
Metastasis is a major cause of cancer mortality and remains a key challenge. Further unraveling the molecular and cellular determinants that enable invasion, dissemination, and colonization will uncover new therapeutic vulnerabilities across the metastatic cascade. Ongoing research also aims to better predict, detect, and prevent lethal metastasis through advanced imaging, liquid biopsies, microenvironment-targeted therapies, and harnessing anti-tumor immunity. With metastatic disease, the adage holds true – an ounce of prevention is worth a pound of cure. As our biological understanding of metastasis grows, more actionable strategies will emerge to spare cancer patients from the devasting effects of tumor spread.