Quick Answer
The most common site of metastasis is the bone. Cancer cells from primary tumors can spread through the bloodstream or lymph system and cause new tumors to form in different parts of the body. For many types of cancer, the bones are the most frequent site of metastasis. The propensity for certain cancers to metastasize to bone is likely related to molecular factors that help circulating tumor cells home in on the bone microenvironment.
Overview of Metastasis
Metastasis refers to the spread of cancer from its original site to other parts of the body. This occurs when cells break off from the primary tumor and enter the bloodstream or lymph system, traveling to new sites where they seed secondary tumors.
The metastasizing process involves several key steps:
- Invasion – Cancer cells invade nearby tissue and enter blood or lymph vessels.
- Intravasation – Cancer cells penetrate the walls of nearby lymph or blood vessels and enter circulation.
- Circulation – Cancer cells travel through the lymphatic system and bloodstream to other areas of the body.
- Adhesion – Cancer cells adhere to the lining of blood vessels at distant sites.
- Extravasation – Cancer cells squeeze through blood vessel walls at distant sites and enter the tissue.
- Proliferation – Cancer cells multiply and form small nodules of cells called micrometastases.
- Angiogenesis – New blood vessels form to supply the metastases with nutrients and oxygen.
Metastasis is a major cause of cancer mortality. While the primary tumor can often be treated with surgery or radiotherapy, metastatic disease is much harder to eradicate.
Common Sites of Metastasis
Although cancer cells can spread to nearly any part of the body, certain sites are more frequent destinations for metastasis based on tumor type:
Bone
The most common site of metastasis overall is the bone. Many types of tumors have an affinity for spreading to the bone marrow and skeletal system. These include:
- Breast cancer
- Prostate cancer
- Lung cancer
- Thyroid cancer
- Kidney cancer
Bone metastases cause pain, fractures, and high blood calcium levels. Treatment options include radiation, surgery, bisphosphonates, and other bone-modifying drugs.
Lung
After bone, the lung is the next most common site of metastasis. Cancers that frequently spread to the lung include:
- Breast cancer
- Colorectal cancer
- Sarcoma
- Melanoma
- Head and neck cancers
Lung metastases can cause shortness of breath, coughing, or hemoptysis (coughing up blood). Treatments range from surgery and radiation therapy to chemotherapy and targeted therapies.
Liver
The liver is a common destination for metastasis, especially from cancers of the digestive tract and abdomen:
- Colorectal cancer
- Pancreatic cancer
- Stomach cancer
- Ovarian cancer
- Melanoma
Liver metastasis can lead to jaundice, abdominal pain, nausea, and liver dysfunction. Treatments include surgical resection, ablation, embolization, and systemic therapies.
Brain
Brain metastasis is most commonly seen in patients with lung cancer, breast cancer, melanoma, renal cell carcinoma, and colorectal cancer. Symptoms depend on the size and location of metastases and include headaches, seizures, vertigo, motor deficits, and cognitive changes. Treatments can include surgery, radiation, chemotherapy, and precision medicines.
Factors Influencing Metastatic Spread
Metastasis is not a random process. Molecular interactions between cancer cells and the local microenvironment appear to guide the patterns of metastatic spread. Factors influencing which sites are most likely to develop metastases include:
Circulatory Patterns
The flow of blood and lymph fluid tends to carry cancer cells to certain areas first. For example, most cells escaping the breast drain into the local lymph nodes before entering the bloodstream. This helps explain why breast cancer often metastasizes first to nearby lymph nodes, bone, liver, and lungs.
Adhesion Molecules
To metastasize, circulating tumor cells must stick to vessel walls at distant sites before extravasating. Different cancer cells express varied adhesion molecules that preferentially bind to receptors on endothelial cells lining the capillaries of common metastatic sites.
Chemokines
Chemokines produced in distant tissues can attract migrating cancer cells expressing the matching chemokine receptors, directing metastasis to specific organs. For example, CCL2/CCR2 interactions are thought to guide breast cancer cells to bone.
Growth Factors
Metastatic sites may express abundant growth factors that fuel the rapid proliferation of cancer cells once they extravasate into the tissue. For example, insulin-like growth factors produced in the bone stimulate the growth of bone metastases.
Extracellular Matrix
The makeup of the extracellular matrix in different tissues promotes the colonization for some cancer cell types over others. Brain tissue, for example, contains extracellular matrix components favoring metastasis from lung and breast cancers.
Immune Surveillance
The activity of the immune system can be heightened or suppressed in different organs. Sites of low immune surveillance may provide a more permissive environment for metastatic growth. For example, pancreatic cancer often metastasizes to the immunosuppressive environment of the liver.
Metastasis Organotropism in Different Cancers
Looking closer, we can identify the most likely metastatic sites for major cancer types:
Lung Cancer Metastasis
Lung cancer most often spreads to the:
- Bone
- Brain
- Liver
- Adrenal glands
Non-small cell lung cancer favors bone and brain metastasis, while small cell lung cancer is more likely spread to the liver and adrenal glands.
Breast Cancer Metastasis
The most common sites of breast cancer metastasis include:
- Bone
- Lung
- Brain
- Liver
Breast cancer preferentially metastasizes to the bone, driven in part by chemokine interactions between CCL2 on osteoblasts and CCR2 on tumor cells.
Prostate Cancer Metastasis
Prostate cancer commonly spreads to:
- Bone
- Lymph nodes
- Lung
- Liver
Up to 90% of men with advanced prostate cancer will develop bone metastases, many of which target the spine.
Colorectal Cancer Metastasis
The most frequent sites of colorectal metastasis are the:
- Liver
- Lung
- Peritoneum
Rectal cancers are more likely to spread to the lung than colon cancers. Synchronous liver metastasis is detected at diagnosis in 20-25% of colorectal cancer patients.
Pancreatic Cancer Metastasis
Pancreatic cancer preferentially metastasizes to the:
- Liver
- Peritoneum
- Lung
Peritoneal carcinomatosis occurs in 40-50% of pancreatic cancer patients, driven by direct spread into the abdominal cavity.
Melanoma Metastasis
Melanoma frequently metastasizes to the:
- Lung
- Brain
- Liver
- Bone
- Skin
Due to its lymphatic spread, melanoma is prone to subcutaneous tissue and skin metastases distant from the primary tumor.
Why Bone is the Most Common Metastatic Site
We’ve seen that across many major cancer types, the skeleton is the most frequently encountered site of metastasis. But why is this? Several key factors drive the propensity of circulating tumor cells to take root and proliferate in bone:
Abundant Blood Supply
The bone marrow receives very high blood flow, increasing the chance that passing cancer cells will become trapped in the sinusoids and stick to bone marrow endothelial cells.
Homing Signals
The abundant extracellular calcium and growth factors like TGF-beta, IGF-1, FGF, and PDGF in the bone microenvironment act as chemotactic factors, drawing cancer cells to the marrow space.
Specialized Niches
The hematopoietic stem cell (HSC) niche and vascular niches of the bone marrow provide a fertile environment for the seeding of cancer stem cells that fuel metastatic proliferation.
Adhesion Factors
Cancer cells express varied adhesion molecules like integrins, cadherins, and CD44 that facilitate binding to components of the bone marrow matrix.
Growth Promoters
Growth factors secreted by osteoblasts, like IGF, TGF-beta, FGF, and BMPs, encourage the sustained expansion of metastatic lesions.
Resistance to Apoptosis
Interactions with bone marrow stromal cells induce paracrine survival signaling in cancer cells, protecting against apoptosis.
Toxic to Immune Cells
Properties of the calcium-rich bone matrix create an immunosuppressive microenvironment hostile to immune cell infiltration and anti-tumor responses.
Diagnosing Metastatic Spread
Detecting metastasis has critical implications for cancer staging and treatment planning. Some techniques used to diagnose metastasis include:
Biopsy
Pathological examination of a tissue sample from a suspected metastatic lesion can provide definitive evidence of metastatic spread. This may be obtained via needle biopsy or surgical biopsy.
Blood Tests
Elevated blood tumor markers like PSA, CEA, or CA-125 can signal potential distant metastasis in some cancers. However, markers alone are not diagnostic.
Molecular Profiling
Comparative molecular profiling of the primary and metastatic tumors helps confirm a clonal relationship when metastasis is ambiguous. Shared mutations indicate a common origin.
Imaging
Imaging modalities like CT, PET/CT, MRI, and bone scintigraphy are routinely used to survey for metastasis in the body. Contrast agents can help spotlight suspicious lesions.
Endoscopy
Endoscopic techniques allow direct visualization of potential metastases inside the abdomen, pelvis, chest, or other organs. Biopsies can be obtained during endoscopy.
Preventing Metastasis
Limiting metastatic spread is a key goal of cancer therapy. Some strategies used to block metastasis include:
Early Detection
Catching the primary tumor when small and localized improves the likelihood of cure before extensive metastasis. Hence the emphasis on cancer screening.
Surgery
Complete surgical resection of the primary tumor can remove a source of new circulating tumor cells and improve metastatic outcomes.
Adjuvant Therapy
Systemic chemotherapy or radiation given after primary treatment destroys residual circulating tumor cells before macrometastases form.
Metastasis Suppressor Genes
Gene therapy to bolster metastasis suppressor genes like NM23, KISS1, and BRMS1 may inhibit the metastatic process.
MMP Inhibitors
Matrix metalloproteinase (MMP) inhibitors can potentially slow metastasis by limiting tumor matrix degradation and invasion.
Immunotherapy
Boosting anti-tumor immune responses may help eliminate circulating tumor cells in the blood and lymph systems to attenuate metastasis.
Molecular Targeting
New drugs blocking metastatic growth pathways driven by TGF-beta, LOX, RANKL, integrins, and other molecules hold promise for disrupting metastatic seeding.
Treating Metastatic Disease
Once metastases develop, treatment focuses on extending life and managing symptoms:
Removal
When possible, isolated metastases may be removed surgically or ablated by radiofrequency or cryoablation. This provides local control.
Radiation
Highly targeted radiotherapy can slow growth and reduce pain from isolated bone, brain, and other metastases.
Chemotherapy
Cytotoxic chemotherapy may shrink or stabilize metastatic disease for some months and palliate symptoms.
Targeted Therapy
Molecularly targeted drugs interrupting metastatic growth signals offer less toxic palliation for some cancers.
Hormone Therapy
Anti-hormonal drugs often effectively control metastatic hormone receptor-positive tumors like breast and prostate cancer.
Immunotherapy
Checkpoint inhibitor immunotherapy boosts the body’s own immune response against metastases for durable control in a subset of patients.
Palliative Care
Relieving pain, providing emotional support, and maintaining quality of life are integral to metastatic cancer care.
Prognosis with Metastatic Disease
Metastasis marks a major turning point in the course of cancer. The prognosis depends on:
- Primary cancer type
- Number and location of metastases
- Disease extent at diagnosis of metastasis
- Treatment options available
- Patient factors like age and performance status
Some metastatic cancers like thyroid or renal cell may progress slowly over years. Others like pancreatic and gastric often progress rapidly with survival of months. In general, solitary metastases have better outcomes than widely disseminated disease. With advancing treatments, 5-year survival over 20% is increasingly common after metastasis diagnosis.
Conclusion
Metastasis to distant organs is responsible for most cancer mortality. The patterns of spread are not random – molecular factors guide metastatic tumors to select organs where circulating tumor cells can thrive. For a variety of reasons, bone is the most common destination of metastasis across many major cancers. Detecting and treating metastases is key, and new therapies are expanding the therapeutic window to combat advanced stage disease. With a personalized approach, outcomes for metastatic cancer continue to improve.